3 intracellular signalling. Flashcards
1
Q
What are the pathways that lead to cell growth and survival upon RTK activation?
A
The Akt pathway and MAP kinase pathway are the two main pathways that lead to cell growth and survival upon RTK activation.
2
Q
How can different receptor homo- or heterodimers affect activation pathways?
A
Different receptor homo- or heterodimers can have different propensities to activate various arms of activation pathways
3
Q
What is the significance of overactivity of TK signaling cascades?
A
As TK signaling cascades are often mitogenic, their overactivity is of great interest for the treatment of cancers.
4
Q
What is the full form of RTK?
A
RTK stands for Receptor Tyrosine Kinase.
5
Q
What is the full form of TK?
A
TK stands for Tyrosine Kinase.
6
Q
What is the main downstream effector of the Akt pathway?
A
The main downstream effector of the Akt pathway is mTORC1.
7
Q
What is the full form of MAP kinase?
A
MAP kinase stands for Mitogen-Activated Protein Kinase.
8
Q
What are the three main components of the MAP kinase pathway?
A
The three main components of the MAP kinase pathway are Ras, Raf, and ERK.
9
Q
What is the function of Ras in the MAP kinase pathway?
A
Ras acts as a molecular switch that is turned on by activated RTKs, which in turn activates downstream effectors including the MAP kinase pathway.
10
Q
What are the different types of receptor dimers?
A
Receptor dimers can be homo- or heterodimers. Homo- dimers consist of two identical receptor subunits, while heterodimers consist of two different subunits.
11
Q
list all the steps in the with how many arrows
A
12
Q
What is the canonical MAPK pathway?
A
The canonical MAPK pathway is a signaling pathway that involves the activation of the small GTPase Ras, which activates a cascade of protein kinases leading to the activation of mitogen-activated protein kinases (MAPKs).
13
Q
What is the first step in the canonical MAPK pathway?
A
The first step in the canonical MAPK pathway is the activation of the small GTPase Ras by a receptor tyrosine kinase (RTK) or a G protein-coupled receptor (GPCR).
14
Q
What is the role of Raf in the canonical MAPK pathway?
A
Raf is a serine/threonine protein kinase that is activated by Ras in the canonical MAPK pathway. Activated Raf then phosphorylates and activates MAP kinase kinase (MEK).
15
Q
What is the role of MEK in the canonical MAPK pathway?
A
MEK is a dual-specificity protein kinase that is activated by Raf in the canonical MAPK pathway. Activated MEK then phosphorylates and activates MAP kinases (MAPKs).
16
Q
What are the three main MAPKs in the canonical MAPK pathway?
which ones are mentioned in the slide 4
A
The three main MAPKs in the canonical MAPK pathway are extracellular signal-regulated kinase 1 and 2 (ERK1/2), c-Jun N-terminal kinase (JNK), and p38 MAPK.
extracellular signal-regulated kinase 1 and 2 (ERK1/2)
17
Q
What is the final outcome of the canonical MAPK pathway?
A
The final outcome of the canonical MAPK pathway depends on the cell type and context, but it often involves the regulation of gene expression, cell growth, and differentiation.
18
Q
What are the different types of signals that can activate MAPK pathways?
A
MAPK pathways can be activated by a wide variety of signals, including growth factors, cytokines, stress signals, and environmental cues.
19
Q
How does the activation of MAPK pathways by multiple signals lead to specificity?
A
The activation of MAPK pathways by multiple signals can lead to specificity through the selective activation of different MAPKs or the activation of different downstream effectors, depending on the nature and timing of the signals.
20
Q
comlete the image
A
21
Q
How is Ras activated by RTK?
A
Ras is activated by RTK through the recruitment and activation of a guanine nucleotide exchange factor (GEF) that catalyzes the exchange of GDP for GTP on Ras.
22
Q
What is the role of Ras in signal transduction pathways?
A
Ras is a small GTPase that acts as a molecular switch, regulating a wide range of signal transduction pathways involved in cell growth, differentiation, and survival.
23
Q
What is the structure of Ras?
Ras is a _________________
A
Ras is a small GTPase that consists of a single polypeptide chain of approximately 21 kDa with a nucleotide-binding pocket and a C-terminal hypervariable region.
24
Q
What is the difference between active and inactive forms of Ras?
A
The active form of Ras is bound to GTP, while the inactive form is bound to GDP. The switch from GDP to GTP is facilitated by a GEF.
25
What is the role of GTPase-activating proteins (GAPs) in Ras signaling?
GAPs are negative regulators of Ras signaling that stimulate the intrinsic GTPase activity of Ras, promoting the hydrolysis of GTP to GDP and thus inactivating Ras.
26
What is the importance of Ras signaling in cancer?
Ras signaling is frequently dysregulated in cancer, with activating mutations in Ras being found in approximately 30% of human tumors. As a result, Ras has been a major target for cancer drug development.
27
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29
What is the role of GEFs in Ras signaling?
GEFs activate Ras by catalyzing the exchange of GDP for GTP, promoting the transition of Ras to its active state.
30
What is the role of GAPs in Ras signaling?
GAPs inactivate Ras by stimulating its intrinsic GTPase activity, promoting the hydrolysis of GTP to GDP and thus returning Ras to its inactive state
31
What is the effect of GDP binding on Ras signaling?
GDP binding to Ras stabilizes the catalytic machinery of Ras and inhibits its interaction with downstream effectors, effectively turning off Ras signaling.
32
What is the importance of the balance between GEF and GAP activity in Ras signaling?
The balance between GEF and GAP activity determines the ______________ and thus the strength of Ras signaling. Dysregulation of this balance can lead ___________________________
The balance between GEF and GAP activity determines the level of active Ras and thus the strength of Ras signaling. Dysregulation of this balance can lead to abnormal cell growth and differentiation, contributing to the development of cancer.
33
What is the consequence of activating mutations in Ras?
Activating mutations in Ras can lead to the _________________, promoting abnormal cell growth and contributing to the development of cancer.
Activating mutations in Ras can lead to the constitutive activation of Ras signaling, promoting abnormal cell growth and contributing to the development of cancer.
34
What is the role of downstream effectors in Ras signaling?
Downstream effectors of Ras signaling, such as the MAPK pathway, transmit the Ras signal to the nucleus, leading to changes in gene expression and cellular responses.
35
Function of the Ras protein
complete this image
36
What is the role of Ras in the initiation of the kinase cascade?
Ras recruits the protein kinase Raf to the plasma membrane, where it can be activated and initiate the kinase cascade.
37
What is the kinase cascade initiated by Ras-Raf?
The kinase cascade initiated by Ras-Raf involves the activation of the downstream kinases MEK and ERK, leading to the regulation of gene expression and cellular responses.
38
What is the role of Raf in the Ras-Raf kinase cascade?
Raf is a serine/threonine kinase that is activated by Ras in the Ras-Raf kinase cascade. Activated Raf then phosphorylates and activates the downstream kinase MEK.
39
What is the role of MEK in the Ras-Raf kinase cascade?
MEK is a _______________
MEK is a dual-specificity protein kinase that is activated by Raf in the Ras-Raf kinase cascade. Activated MEK then phosphorylates and activates the downstream kinase ERK.
40
What is the role of ERK in the Ras-Raf kinase cascade?
ERK is a serine/threonine kinase that is activated by MEK in the Ras-Raf kinase cascade. Activated ERK then phosphorylates a variety of downstream targets, leading to changes in gene expression and cellular responses.
41
How does Ras link to the MAPK signal cascade?
Ras activates the MAPK signal cascade by activating a series of kinases that ultimately lead to the activation of mitogen-activated protein kinases (MAPKs).
42
What is the first kinase activated in the MAPK signal cascade?
The first kinase activated in the MAPK signal cascade is a mitogen-activated protein kinase kinase kinase (MAPKKK), which is often activated by phosphorylation.
43
What is the role of MAPKKKs in the MAPK signal cascade?
MAPKKKs phosphorylate and activate a second class of kinase called mitogen-activated protein kinase kinase (MAPKK).
44
What is the role of MAPKKs in the MAPK signal cascade?
MAPKKs phosphorylate and activate the third class of kinase called MAPKs.
45
What is the function of MAPKs in the MAPK signal cascade?
MAPKs phosphorylate and activate downstream targets, such as transcription factors, leading to changes in gene expression and cellular responses.
46
What is the difference between MAPKKKs and MAPKKs in terms of kinase activity?
MAPKKKs and MAPKs are serine/threonine kinases, while MAPKKs are threonine/tyrosine kinases.
47
What is the importance of the MAPK signal cascade in cellular responses?
The MAPK signal cascade is involved in a wide range of cellular responses, including cell growth, differentiation, survival, and apoptosis. Dysregulation of this pathway can contribute to the development of cancer and other diseases.
48
complete this image on ras link to mapk signal cascade
49
What is the MAP kinase pathway involving Ras?
The MAP kinase pathway involving Ras is a signaling pathway that regulates cellular responses such as cell growth, differentiation, and survival.
50
What is the role of Raf in the MAP kinase pathway involving Ras?
Raf is a MAPKKK that is activated by Ras in the MAP kinase pathway involving Ras. Activated Raf then phosphorylates and activates the downstream MAPKK, MEK.
51
What is the role of MEK in the MAP kinase pathway involving Ras?
MEK is a MAPKK that is activated by Raf in the MAP kinase pathway involving Ras. Activated MEK then phosphorylates and activates the downstream MAPK, ERK.
52
What is the role of ERK in the MAP kinase pathway involving Ras?
ERK is a MAPK that is activated by MEK in the MAP kinase pathway involving Ras. Activated ERK then phosphorylates a variety of downstream targets, including the ribosomal S6 kinase (RSK).
53
What is the function of RSK in the MAP kinase pathway involving Ras?
RSK is a serine/threonine protein kinase that is a major target of ERK in the MAP kinase pathway involving Ras. RSK regulates a variety of cellular responses, including cell growth and differentiation.
54
What is the significance of the MAP kinase pathway involving Ras in cancer?
The MAP kinase pathway involving Ras is frequently dysregulated in cancer, with mutations in Ras or other components of the pathway contributing to the development and progression of cancer. As a result, this pathway has been a major target for cancer drug development.
55
complete this image on map kinase pathway involving ras
56
57
What is the role of scaffolding proteins in signaling complex assembly?
Scaffolding proteins play a critical role in organizing multiprotein signaling complexes by facilitating the assembly of specific signaling components and regulating the kinetics, amplitude, and localization of signaling events.
58
What is KSR?
KSR (kinase suppressor of Ras) is a scaffolding protein that plays a role in the assembly of the MAP kinase signaling complex, regulating the activation of MEK and ERK.
59
What is the function of KSR in the MAP kinase signaling pathway?
KSR functions as a scaffold that brings together the MAP kinase signaling components, promoting the activation of MEK and ERK and regulating the kinetics, amplitude, and localization of signaling events.
60
How does KSR regulate the specificity of the MAP kinase signaling pathway?
KSR regulates the specificity of the MAP kinase signaling pathway by targeting MEK and ERK to specific substrates and facilitating communication with other signaling pathways, leading to specific biological responses.
61
What is the importance of scaffolding proteins in signal transduction?
Scaffolding proteins play a critical role in the regulation of signal transduction by _____________, _________________ and kinetics, and ___________________. Dysregulation of scaffolding proteins has been implicated in ____________________
Scaffolding proteins play a critical role in the regulation of signal transduction by organizing signaling complexes, modulating signaling amplitude and kinetics, and promoting cross-talk between signaling pathways. Dysregulation of scaffolding proteins has been implicated in a range of diseases, including cancer and neurodegenerative disorders.
62
complete this image on scaffolding
63
What is cross-talk between signaling pathways?
Cross-talk between signaling pathways refers to the interactions and communication between different signaling cascades, resulting in modulation of signaling responses.
64
How does cross-talk between signaling pathways affect specificity of response?
Cross-talk between signaling pathways can lead to a lack of specificity of response, as the activation of one signaling pathway can interfere with or modulate the activation of another pathway.
65
What is the mechanism by which scaffold proteins limit cross-talk between signaling pathways?
Scaffold proteins play a critical role in limiting cross-talk between signaling pathways by determining _____________, ensuring ______________________.
Scaffold proteins play a critical role in limiting cross-talk between signaling pathways by determining which substrate proteins are within the vicinity of the kinases, ensuring that specific substrates are targeted by the appropriate signaling cascade.
66
What is the importance of scaffold proteins in regulating cross-talk between signaling pathways?
Scaffold proteins play a critical role in ______________ and _______________, ensuring that signaling responses are appropriately regulated and coordinated. Dysregulation of scaffold proteins has been implicated in a range of diseases, including cancer and neurodegenerative disorders.
Scaffold proteins play a critical role in maintaining signaling specificity and limiting cross-talk between signaling pathways, ensuring that signaling responses are appropriately regulated and coordinated. Dysregulation of scaffold proteins has been implicated in a range of diseases, including cancer and neurodegenerative disorders.
67
What are some examples of cross-talk between signaling pathways?
Examples of cross-talk between signaling pathways include the interaction between the MAP kinase pathway and the PI3 kinase pathway, the interaction between the NF-kB pathway and the JAK/STAT pathway, and the interaction between the Notch pathway and the Wnt pathway.
68
What are the effects of dysregulated Ras/MAPK signaling in disease?
Dysregulated Ras/MAPK signaling can contribute to a range of diseases, including cancer, cardiovascular disease, and neurodegenerative disorders.
69
Why is Ras frequently mutated in human tumors?
Ras is frequently mutated in human tumors because it is one of the genes most commonly mutated in cancer, with mutations often leading to the loss of GTP-hydrolyzing ability and the trapping of Ras in an "on" position, leading to continual stimulation of cell proliferation.
70
What are the three Ras proteins found in mammalian cells?
The three Ras proteins found in mammalian cells are H-ras, K-ras, and N-ras.
71
What is the mechanism by which Ras is activated?
Ras is activated by the binding of GTP, which leads to a conformational change that allows it to interact with downstream effector proteins.
72
What are some of the drugs that target the Ras/MAPK signaling pathway in cancer?
New signal transduction inhibitor drugs that target nodes in the pathway, such as Raf kinase inhibitors, are being developed to treat cancer by blocking dysregulated Ras/MAPK signaling.
73
What is the function of phospholipids in signal transduction?
Phospholipids play a critical role in signal transduction by serving as signaling molecules and modulating the localization and activity of downstream signaling components.
74
What are the phospholipid classes involved in signal transduction?
The phospholipid classes involved in signal transduction include phosphatidylserine (PS), phosphatidylcholine (PC), phosphatidylethanolamine (PE), and phosphatidylinositol (PI).
75
complete this image
76
what structure is this?
what are the other sub-structures?
77
fill in the missing stuff
78
What is the role of PLC in signal transduction?
PLC (phospholipase C) is an enzyme that plays a critical role in signal transduction by hydrolyzing phosphatidylinositol 4,5-bisphosphate (PIP2) to generate the second messengers diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP3).
79
What is the function of PIP2 in signal transduction?
PIP2 (phosphatidylinositol 4,5-bisphosphate) is a signaling molecule that plays a critical role in the activation of a wide range of signaling pathways, including the PI3K/Akt and PLC signaling pathways.
80
What is the mechanism by which PLC generates DAG and IP3 from PIP2?
PLC hydrolyzes PIP2 to generate DAG and IP3. IP3 is a water-soluble molecule that is released into the cytosol, where it binds to and activates IP3 receptors on the endoplasmic reticulum, leading to the release of calcium ions. DAG, on the other hand, remains in the plasma membrane and activates downstream signaling components, such as protein kinase C (PKC).
81
What is the role of DAG in signal transduction?
DAG (diacylglycerol) is a signaling molecule that plays a critical role in the activation of downstream signaling components, such as protein kinase C (PKC), by promoting their translocation to the plasma membrane and activation.
82
What is the role of calcium ions in signal transduction?
Calcium ions play a critical role in signal transduction by regulating a wide range of cellular responses, including muscle contraction, neurotransmitter release, and gene expression. Calcium ions are typically released from intracellular stores, such as the endoplasmic reticulum, in response to various signaling events.
83
COMPLETE THE BLACKED OUT STUFF
84
_______________________serves as a key second messenger in the PI3K/Akt signaling pathway, promoting the recruitment and activation of downstream signaling components, such as Akt, to regulate cellular responses such as cell growth, survival, and metabolism.
PIP3 serves as a key second messenger in the PI3K/Akt signaling pathway, promoting the recruitment and activation of downstream signaling components, such as Akt, to regulate cellular responses such as cell growth, survival, and metabolism.
85
What are some of the different PIPs involved in signal transduction?
Some of the different PIPs involved in signal transduction include ___________, ________________, _____________________, ______________________, _________________________, and __________________________.
Some of the different PIPs involved in signal transduction include phosphatidylinositol 3-phosphate (PI3P), phosphatidylinositol 4-phosphate (PI4P), phosphatidylinositol 5-phosphate (PI5P), phosphatidylinositol 3,4-bisphosphate (PI3,4P2), phosphatidylinositol 4,5-bisphosphate (PIP2), and phosphatidylinositol 3,4,5-trisphosphate (PIP3).
86
What is the role of PIPs in membrane recruitment of signaling proteins?
PIPs (phosphatidylinositols) play a critical role in the ___________ and ______________ to specific membranes, serving as _________________ for a wide range of downstream signaling components.
PIPs (phosphatidylinositols) play a critical role in the recruitment and localization of signaling proteins to specific membranes, serving as docking sites for a wide range of downstream signaling components.
87
What is the mechanism by which PIPs recruit signaling proteins to membranes?
PIPs recruit signaling proteins to membranes through their ability to ______________________, which bind to PIPs with high specificity and affinity, ensuring precise membrane localization of signaling components.
PIPs recruit signaling proteins to membranes through their ability to interact with specific protein domains, such as pleckstrin homology (PH) domains, which bind to PIPs with high specificity and affinity, ensuring precise membrane localization of signaling components.
88
What are some of the downstream signaling components that are recruited to membranes by PIPs?
Some of the downstream signaling components that are recruited to membranes by PIPs include _________, _____________, and various small ________________, such as __________ and ___________.
Some of the downstream signaling components that are recruited to membranes by PIPs include Akt, protein kinase C (PKC), and various small GTPases, such as Rho and Arf.
89
What is the role of PH domains in PIP-mediated membrane recruitment?
PH domains are protein domains that play a critical role in the recognition and binding of PIPs, ensuring the precise membrane localization of downstream signaling components and the appropriate activation of signaling pathways.
90
What are phosphoinositide targeting domains?
Phosphoinositide targeting domains are protein domains that specifically recognize and bind to different phosphoinositide lipids, enabling the precise localization and recruitment of downstream signaling components to specific membranes.
91
What are some of the different phosphoinositide targeting domains?
Some of the different phosphoinositide targeting domains include PH (pleckstrin homology), FYVE (Fab1, YOTB, Vac1, EEA1), PX (Phox homology), FERM (protein 4.1/ezrin/radixin/moesin), ANTH (AP180 N-terminal homology), ENTH (Epsin N-terminal homology), and tubby domains.
92
What is the function of the FYVE and PX domains in phosphoinositide recognition?
The FYVE and PX domains are protein domains that recognize and bind to phosphatidylinositol 3-phosphate (PtdIns(3)P), enabling the precise localization of downstream signaling components to endosomal and lysosomal membranes.
93
What is the function of the PH domain in phosphoinositide recognition?
The PH domain is a protein domain that recognizes and binds to a range of phosphoinositide lipids, including PtdIns(4)P, PtdIns(3,4)P2, PtdIns(4,5)P2, and PtdIns(3,4,5)P3, enabling the precise localization of downstream signaling components to specific membranes.
94
What are some of the downstream signaling components that are recruited to membranes by phosphoinositide targeting domains?
Some of the downstream signaling components that are recruited to membranes by phosphoinositide targeting domains include small GTPases, such as Arf and Rac, protein kinases, such as Akt and PKC, and various cytoskeletal proteins, such as ezrin, radixin, and moesin.
95
What is the importance of phosphoinositide targeting domains in signal transduction?
Phosphoinositide targeting domains play a critical role in the regulation of signal transduction by ensuring the precise localization and activation of downstream signaling components, enabling specific signaling responses to be elicited in response to diverse extracellular stimuli.
96
MATCH WITH THE TARGETING DOMAIN
97
What is phosphatidylinositol 3-kinase (PI3K)?
PI3K is a family of intracellular lipid kinases that play a critical role in signal transduction by _________________, _______________ and a___________________, such as Akt, to regulate cellular responses such as cell growth, survival, and metabolism.
PI3K is a family of intracellular lipid kinases that play a critical role in signal transduction by phosphorylating phosphatidylinositol lipids, enabling the recruitment and activation of downstream signaling components, such as Akt, to regulate cellular responses such as cell growth, survival, and metabolism.
98
What are some of the functions of PI3K in signal transduction?
PI3K transduces signals for a wide range of cellular responses, including proliferation, migration, survival, and glucose homeostasis, by regulating the activation and localization of downstream signaling components.
99
What are the different classes of PI3K?
There are three classes of PI3K: Class I, Class II, and Class III. Class IA PI3Ks are activated by oncogenic receptor tyrosine kinases (RTKs) and play a central role in cancer.
100
What is the mechanism by which PI3K regulates signal transduction?
PI3K regulates signal transduction by _______________phosphatidylinositol lipids, such as phosphatidylinositol 4,5-bisphosphate (PIP2), to generate __________________________, which serves as a key second messenger in the recruitment and _______________components, such as Akt.
PI3K regulates signal transduction by phosphorylating phosphatidylinositol lipids, such as phosphatidylinositol 4,5-bisphosphate (PIP2), to generate phosphatidylinositol 3,4,5-trisphosphate (PIP3), which serves as a key second messenger in the recruitment and activation of downstream signaling components, such as Akt.
101
What is the importance of PI3K in cancer?
PI3K plays a central role in cancer by regulating cellular processes such as proliferation, survival, and metabolism, and is commonly mutated in a wide range of human tumors. Understanding the roles of PI3K in cancer may provide new targets for therapeutic intervention in this disease.
102
COMPLETE THE MISSING STUFFS
103
What is the structure of the PI3K molecule?
The PI3K molecule is composed of heterodimers of _____________ and ___________________proteins that work together to transduce signals for _____________________.
The PI3K molecule is composed of heterodimers of regulatory subunit (p85) and catalytic subunit (p110) proteins that work together to transduce signals for a wide range of cellular responses.
104
What is the role of the regulatory subunit (p85) in PI3K?
The regulatory subunit (p85) of PI3K plays a critical role in binding to ____________________ and ______________________, enabling the recruitment and activation of the __________________.
The regulatory subunit (p85) of PI3K plays a critical role in binding to receptor tyrosine kinases (RTKs) and other signaling proteins, enabling the recruitment and activation of the catalytic subunit (p110).
105
What is the role of the catalytic subunit (p110) in PI3K?
The catalytic subunit (p110) of PI3K plays a critical role in ____________________ phosphatidylinositol lipids, such as phosphatidylinositol 4,5-bisphosphate (PIP2), to generate _________________, which serves as a key second messenger in the recruitment and activation of downstream signaling components.
The catalytic subunit (p110) of PI3K plays a critical role in phosphorylating phosphatidylinositol lipids, such as phosphatidylinositol 4,5-bisphosphate (PIP2), to generate phosphatidylinositol 3,4,5-trisphosphate (PIP3), which serves as a key second messenger in the recruitment and activation of downstream signaling components.
106
WHAT IS THIS IMAGE DESCRIBING?
AND COMPLETE THE IMAGE
107
What is the downstream effector of the PI3K pathway?
The downstream effector of the PI3K pathway is Akt (also known as protein kinase B), which plays a central role in regulating a wide range of cellular responses, including cell growth, survival, and metabolism.
108
How is Akt recruited to the membrane in the PI3K pathway?
Akt is recruited to the membrane by phosphatidylinositol 3,4,5-trisphosphate (PIP3), which is generated by the activity of PI3K on phosphatidylinositol 4,5-bisphosphate (PIP2). Akt is specifically recruited to the membrane via its pleckstrin homology (PH) domain.
109
What is the mechanism by which Akt is activated in the PI3K pathway?
Akt is activated by phosphorylation at two key residues: ________________ and ___________________. ________________ is phosphorylated by the protein kinase PDK1, which is also recruited to the membrane by its PH domain, while _______________ is phosphorylated by the mTORC2 complex.
Akt is activated by phosphorylation at two key residues: threonine 308 (Thr308) and serine 473 (Ser473). Thr308 is phosphorylated by the protein kinase PDK1, which is also recruited to the membrane by its PH domain, while Ser473 is phosphorylated by the mTORC2 complex.
110
What is the role of Akt in cell growth and survival?
Akt plays a critical role in regulating cell growth and survival by phosphorylating and modulating the activity of a wide range of downstream targets, including enzymes involved in metabolism and transcription factors involved in gene expression.
111
What is the importance of Akt in disease?
Dysregulation of Akt signaling has been implicated in a range of diseases, including cancer, diabetes, and cardiovascular disease, highlighting the critical role of this pathway in maintaining normal cellular homeostasis.
112
What are the factors that dictate the level of Akt activity in the PI3K pathway?
The level of Akt activity in the PI3K pathway is dictated by a number of factors, including the ____________ and the ____________, such as phosphatidylinositol 3,4,5-trisphosphate (PIP3), which recruits Akt to the membrane and promotes its activation.
The level of Akt activity in the PI3K pathway is dictated by a number of factors, including the activation status of PI3K and the levels of its lipid products, such as phosphatidylinositol 3,4,5-trisphosphate (PIP3), which recruits Akt to the membrane and promotes its activation.
113
How does PI3K activation status affect Akt activity?
PI3K activation status is a critical determinant of Akt activity, as PI3K generates the ______________that recruit Akt to the membrane and activate it by ________________. Dysregulation of PI3K activity, either through genetic mutations or altered signaling pathways, can lead to __________________ and contribute to disease.
PI3K activation status is a critical determinant of Akt activity, as PI3K generates the lipid products that recruit Akt to the membrane and activate it by phosphorylation. Dysregulation of PI3K activity, either through genetic mutations or altered signaling pathways, can lead to aberrant activation of Akt and contribute to disease.
114
What is the role of PIP3 in regulating Akt activity?
PIP3 plays a critical role in regulating Akt activity by recruiting Akt to the membrane, where it is ____________ and _____________ by PDK1 and mTORC2. The levels of PIP3 are tightly regulated by the activity of _________ and _____________, which maintain a balance between PIP3 __________ and _____________
PIP3 plays a critical role in regulating Akt activity by recruiting Akt to the membrane, where it is phosphorylated and activated by PDK1 and mTORC2. The levels of PIP3 are tightly regulated by the activity of PI3K and phosphatases, which maintain a balance between PIP3 generation and degradation
115
What are some of the downstream targets of Akt in the PI3K pathway?
Akt phosphorylates and modulates the activity of a wide range of downstream targets, including enzymes involved in metabolism and transcription factors involved in gene expression. Some of the key targets of Akt include ____________, ____________, and the ______________ family of transcription factors.
Akt phosphorylates and modulates the activity of a wide range of downstream targets, including enzymes involved in metabolism and transcription factors involved in gene expression. Some of the key targets of Akt include glycogen synthase kinase 3 (GSK3), mTORC1, and the forkhead box O (FOXO) family of transcription factors.
116
COMPLETE THE DOWNSTREAM TARGETS OF AKT
117
What is the role of Akt in anti-apoptosis?
Akt plays a critical role in promoting cell survival and inhibiting apoptosis by _________ and _____________ the activity of a wide range of downstream targets involved in the regulation of gene expression, metabolism, and cell signaling.
Akt plays a critical role in promoting cell survival and inhibiting apoptosis by phosphorylating and modulating the activity of a wide range of downstream targets involved in the regulation of gene expression, metabolism, and cell signaling.
118
What are some of the downstream targets of Akt in the anti-apoptotic pathway?
Some of the downstream targets of Akt in the anti-apoptotic pathway include the __________, the _______________, the ________________, ____________________, and _________________.
Some of the downstream targets of Akt in the anti-apoptotic pathway include the transcription factor FOXO, the pro-apoptotic protein BAD, the nuclear factor κB (NF-κB), the tumor suppressor protein p53, and the enzyme glycogen synthase kinase 3 (GSK3).
119
How does Akt phosphorylation of FOXO contribute to anti-apoptosis?
Akt phosphorylates FOXO and ____________, preventing it from activating _________ and ___________ genes. This promotes cell survival by inhibiting ______________.
Akt phosphorylates FOXO and sequesters it in the cytoplasm, preventing it from activating anti-cell cycle and pro-apoptotic genes. This promotes cell survival by inhibiting cell death pathways.
120
How does Akt phosphorylation of BAD contribute to anti-apoptosis?
Akt phosphorylates BAD, a __________, and promotes its __________ and ____________ preventing it from inducing apoptosis. This contributes to the anti-apoptotic effects of Akt.
Akt phosphorylates BAD, a pro-apoptotic protein, and promotes its sequestration and inactivation, preventing it from inducing apoptosis. This contributes to the anti-apoptotic effects of Akt.
121
How does Akt phosphorylation of MDM2 contribute to anti-apoptosis?
Akt phosphorylates MDM2, which leads to ________________. This drives ________________ and inhibits apoptosis, contributing to the anti-apoptotic effects of Akt.
Akt phosphorylates MDM2, which leads to the degradation of the tumor suppressor protein p53. This drives cell cycle progression and inhibits apoptosis, contributing to the anti-apoptotic effects of Akt.
122
What are some downstream effects of PI3K signaling that are independent of Akt?
While Akt is a central effector of the PI3K pathway, there are also several downstream effects of PI3K signaling that are independent of Akt, including regulation of cell motility and cytoskeletal dynamics via activation of the small GTPases _________ and ___________________
While Akt is a central effector of the PI3K pathway, there are also several downstream effects of PI3K signaling that are independent of Akt, including regulation of cell motility and cytoskeletal dynamics via activation of the small GTPases Rac and Cdc42.
123
What is the role of Rac and Cdc42 in PI3K signaling?
Rac and Cdc42 are small GTPases that are activated downstream of PI3K signaling and play a critical role in regulating __________ and __________ dynamics. These proteins are involved in the formation of ____________ structures such as filopodia and ___________________, which are essential for cell ____________ and _____________.
Rac and Cdc42 are small GTPases that are activated downstream of PI3K signaling and play a critical role in regulating cell motility and cytoskeletal dynamics. These proteins are involved in the formation of actin-based structures such as filopodia and lamellipodia, which are essential for cell migration and invasion.
124
How does PI3K signaling activate Rac and Cdc42?
PI3K signaling activates Rac and Cdc42 by generating __________________________, which recruit and activate ___________________ that promote the activation of Rac and Cdc42.
PI3K signaling activates Rac and Cdc42 by generating lipid products such as phosphatidylinositol 3,4,5-trisphosphate (PIP3), which recruit and activate guanine nucleotide exchange factors (GEFs) that promote the activation of Rac and Cdc42.
125
What is the importance of PI3K signaling independent of Akt in disease?
Dysregulation of PI3K signaling independent of Akt has been implicated in a range of diseases, including cancer and cardiovascular disease, highlighting the critical role of this pathway in maintaining normal cellular homeostasis. Targeting downstream effectors of PI3K signaling, such as Rac and Cdc42, may provide new opportunities for therapeutic intervention in these diseases.
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What is the link between the PI3K pathway and cancer?
PI3K activity was first found to be associated with viral oncogenes and then with mammalian proto-oncogenes. Overactive PI3K signaling has been implicated in a wide range of human cancers, with a very high frequency of somatic mutations in the ___________________ observed in many cancer types.
PI3K activity was first found to be associated with viral oncogenes and then with mammalian proto-oncogenes. Overactive PI3K signaling has been implicated in a wide range of human cancers, with a very high frequency of somatic mutations in the p110 subunit gene (PIK3CA) observed in many cancer types.
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What are some of the mutations commonly found in the PI3K pathway in cancer?
Three "hot spot" mutations in the PIK3CA gene account for around 80% of _________________ observed in human cancers. These mutations lead to the ________________ and can result in ______________, promoting cell proliferation and survival.
Three "hot spot" mutations in the PIK3CA gene account for around 80% of all somatic mutations observed in human cancers. These mutations lead to the overactivation of PI3K signaling and can result in growth factor-independent activation of Akt, promoting cell proliferation and survival.
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What is the potential for targeted therapy in PI3K pathway-driven cancers?
Targeted therapy aimed at specifically inhibiting the _____________has shown promise in preclinical and clinical trials. Several drugs that target ____________have been developed, with some showing efficacy in cancer treatment. However, the _______________ and __________________ in the PI3K pathway has made it challenging to develop effective targeted therapies with limited off-target effects.
Targeted therapy aimed at specifically inhibiting the mutated p110 subunit of PI3K has shown promise in preclinical and clinical trials. Several drugs that target PI3K have been developed, with some showing efficacy in cancer treatment. However, the high degree of complexity and redundancy in the PI3K pathway has made it challenging to develop effective targeted therapies with limited off-target effects.
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What is the importance of the PI3K pathway in cancer biology?
The PI3K pathway plays a critical role in cancer biology, regulating key cellular processes such as proliferation, survival, and motility. Dysregulation of this pathway can contribute to the development and progression of cancer, making it an attractive target for therapeutic intervention. However, the complexity and redundancy of the pathway pose significant challenges to the development of effective targeted therapies.
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What is the E545K mutation in the p110 subunit of PI3K?
The E545K mutation is a specific mutation in the p110 subunit of PI3K that leads to enhanced activation of _______________. This mutation results in a ________________ at position ___________, where ______________is replaced by _________________
The E545K mutation is a specific mutation in the p110 subunit of PI3K that leads to enhanced activation of the PI3K pathway. This mutation results in a single amino acid substitution at position 545, where glutamic acid is replaced by lysine.
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What is the role of the PI3K pathway in ovarian and cervical cancers?
The PI3K pathway is upregulated in ovarian and cervical cancers, leading to ___________, ____________, and_______________. Dysregulation of this pathway is frequently observed in these cancer types and is associated with poor clinical outcomes
The PI3K pathway is upregulated in ovarian and cervical cancers, leading to enhanced cell proliferation, survival, and motility. Dysregulation of this pathway is frequently observed in these cancer types and is associated with poor clinical outcomes
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What is the significance of Akt in cancer?
Akt is a central effector of the PI3K pathway and plays an important role in many types of cancer. Akt activation has been observed in a large number of cancers, including ___________, _____________, ____________, and _____________. Akt promotes ___________ by influencing the expression of _________ and ___________, and also plays a critical role in resistance of cancer cells to ___________________ by countering the __________ and ____________ induced by these agents.
Akt is a central effector of the PI3K pathway and plays an important role in many types of cancer. Akt activation has been observed in a large number of cancers, including gastric, ovarian, pancreatic, and breast cancer. Akt promotes angiogenesis by influencing the expression of VEGF and HIF-1, and also plays a critical role in resistance of cancer cells to anti-neoplastic agents by countering the cell stress and apoptosis induced by these agents.
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____________________is a negative regulator of the PI3K pathway and acts as a tumor suppressor by inhibiting Akt activation. ____________ is often mutated or deleted in a variety of human cancers, resulting in the loss of its function and leading to the dysregulation of PI3K signaling. The loss of _________________ is particularly common in ___________cancer, __________ cancer, and ________________.
PTEN is a negative regulator of the PI3K pathway and acts as a tumor suppressor by inhibiting Akt activation. PTEN is often mutated or deleted in a variety of human cancers, resulting in the loss of its function and leading to the dysregulation of PI3K signaling. The loss of PTEN function is particularly common in prostate cancer, endometrial cancer, and glioblastoma.
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What are some potential therapeutic strategies targeting the PI3K pathway in cancer?
Targeting the PI3K pathway has emerged as a promising strategy for cancer therapy. Several drugs that inhibit PI3K, Akt, or downstream effectors of the pathway have been developed and are being tested in preclinical and clinical trials. These drugs have shown promising results in treating various types of cancer, but their clinical utility may be limited by toxicity and off-target effects.
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What is the role of PTEN in the PI3K pathway?
PTEN is a central negative regulator of the PI3K pathway. It acts as a ___________ that ___________ the lipid product of PI3K, ____________, back to _____________. By doing so, PTEN counteracts the effect of PI3K and inhibits the activation of downstream effectors such as ______________.
PTEN is a central negative regulator of the PI3K pathway. It acts as a phosphatase that dephosphorylates the lipid product of PI3K, phosphatidylinositol 3,4,5-trisphosphate (PIP3), back to phosphatidylinositol 4,5-bisphosphate (PIP2). By doing so, PTEN counteracts the effect of PI3K and inhibits the activation of downstream effectors such as Akt.
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COMPLETE THE INFORMATION ON THE SLIDE
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What is PTEN?
PTEN stands for "phosphatase and tensin homologue deleted on chromosome 10". It is a tumor suppressor gene that encodes a phosphatase enzyme that acts as a negative regulator of the PI3K pathway.
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What is the significance of PTEN in cancer?
Loss of PTEN function is observed in a wide spectrum of human cancers, including prostate, breast, lung, colon, endometrial, and brain cancers. PTEN inactivation leads to the accumulation of its substrate, PIP3, and the hyperactivation of the PI3K/Akt signaling pathway, promoting cell proliferation, survival, and motility. PTEN is frequently mutated, deleted, or silenced in sporadic cancers, and germline mutations in PTEN predispose individuals to cancer. PTEN is regarded as one of the most commonly mutated tumor suppressor genes in human cancers, rivaling p53.
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What are some potential therapeutic strategies targeting PTEN in cancer?
Restoring PTEN function or inhibiting downstream effectors of the PI3K/Akt pathway are emerging as promising therapeutic strategies for cancer. Several drugs that aim to restore PTEN expression, stability, or activity are being developed and tested in preclinical and clinical trials. These drugs have shown promising results in restoring sensitivity to chemotherapy and targeted therapy in cancer cells with PTEN deficiency.
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Why is the PI3K/Akt pathway a potential target for cancer therapy?
The PI3K/Akt pathway is frequently dysregulated in cancer, with increased signaling associated with tumor growth, survival, and resistance to therapy. Targeting the PI3K/Akt pathway is therefore a promising strategy for cancer therapy.
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What are some PI3K pathway inhibitors?
Several classes of drugs that target the PI3K/Akt pathway are being developed and tested in preclinical and clinical trials. These include ______________, ______________, and _____________. Some examples of these drugs are _________, ____________, _____________,_____________, and ______________.
Several classes of drugs that target the PI3K/Akt pathway are being developed and tested in preclinical and clinical trials. These include isoform-selective PI3K inhibitors, dual PI3K/mTOR inhibitors, and Akt inhibitors. Some examples of these drugs are PI-103, NVP-BEZ235, idelalisib, duvelisib, and ipatasertib.
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What are the challenges and opportunities in developing PI3K pathway inhibitors?
One of the challenges in developing PI3K pathway inhibitors is achieving isoform selectivity and avoiding off-target effects. The PI3K pathway is highly complex and interconnected with other signaling pathways, making it difficult to selectively target one component without affecting others. Another challenge is the development of drug resistance, as cancer cells can adapt and develop alternative mechanisms to activate the PI3K pathway. However, the potential benefits of targeting the PI3K pathway are significant, and there is a growing number of drugs that show promise in preclinical and clinical trials.
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What are Akt inhibitors?
Akt inhibitors are drugs that target the Akt family of kinases, which are downstream effectors of the PI3K pathway.
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What are the challenges in developing Akt inhibitors?
One of the challenges in developing Akt inhibitors is achieving isoform selectivity and avoiding off-target effects. The Akt family consists of three isoforms (Akt1, Akt2, and Akt3) with distinct functions and expression patterns in different tissues and tumors. Another challenge is the development of drug resistance, as cancer cells can adapt and develop alternative mechanisms to activate the PI3K pathway. However, the potential benefits of targeting Akt are significant, and there is a growing number of drugs that show promise in preclinical and clinical trials.
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What are some examples of Akt inhibitors?
Some examples of Akt inhibitors include __________, ____________, and ______________. ________________ is an ATP-competitive Akt inhibitor that inhibits the activity of all three Akt isoforms and is currently in clinical trials. ____________________ is an irreversible Akt inhibitor that binds to a specific site on the Akt kinase domain and confers selectivity._________________ are highly selective and can be modified for cell entry and stability.
Some examples of Akt inhibitors include GSK690693, lactoquinomycin, and Akt peptide pseudosubstrates. GSK690693 is an ATP-competitive Akt inhibitor that inhibits the activity of all three Akt isoforms and is currently in clinical trials. Lactoquinomycin is an irreversible Akt inhibitor that binds to a specific site on the Akt kinase domain and confers selectivity. Akt peptide pseudosubstrates are highly selective and can be modified for cell entry and stability.
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What are some considerations for using Akt inhibitors in cancer therapy?
One consideration for using Akt inhibitors in cancer therapy is tissue- and tumor-type specificity. The expression and activation of Akt isoforms can vary depending on the tissue and tumor type, and different isoforms may have different roles in cancer development and progression. Another consideration is the potential for off-target effects and drug resistance, as cancer cells can develop alternative mechanisms to activate the PI3K pathway. However, the development of isoform-selective Akt inhibitors and combination therapies targeting multiple components of the PI3K pathway may help overcome these challenges.
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What is combination therapy for targeting the PI3K/Akt pathway?
Combination therapy involves the use of multiple drugs or treatment modalities to target different components of the PI3K/Akt pathway. This approach can overcome the challenges of primary and secondary resistance to targeted therapy, which can result from mutations in the target or bypass of the targeted pathway. Combination therapy can involve dual targeting of the same molecule, such as _________ and ___________, or dual targeting of different molecules, such as __________ and _______,_______, __________, or _______________.
Combination therapy involves the use of multiple drugs or treatment modalities to target different components of the PI3K/Akt pathway. This approach can overcome the challenges of primary and secondary resistance to targeted therapy, which can result from mutations in the target or bypass of the targeted pathway. Combination therapy can involve dual targeting of the same molecule, such as anti-EGFR antibodies and small molecule TKIs, or dual targeting of different molecules, such as mTOR inhibitors and IGF1R, PI3K, Akt, or MAPK inhibitors.
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What are the benefits of combination therapy for targeting the PI3K/Akt pathway?
HINT: For example, prolonged mTOR inhibition can lead to feedback activation of Akt and MAPK pathways, which can be counteracted by combining mTOR inhibitors with PI3K, Akt, or MAPK inhibitors. Dual targeting of the same molecule can also enhance the efficacy and specificity of targeted therapy, as seen in the combination of anti-EGFR antibodies and small molecule TKIs.
Combination therapy can provide greater efficacy and specificity than monotherapy, as it targets multiple components of the PI3K/Akt pathway and can overcome the limitations of single agents.
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WHAT DRUGS ARE UNDER anti-EGFR Ab AND small molecule TKI
anti-EGFR Ab (trastuzumab) + small molecule TKI (lapatinib)
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What are some examples of combination therapy for targeting the PI3K/Akt pathway?
Some examples of combination therapy for targeting the PI3K/Akt pathway include the combination of mTOR inhibitors with IGF1R, PI3K, Akt, or MAPK inhibitors, as well as the combination of anti-EGFR antibodies and Akt/mTOR inhibitors.
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What is chemoresistance in cancer cells?
Chemoresistance is when cancer cells can resist the effects of chemotherapy and other anti-cancer treatments.
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______ and ___________ contribute to chemoresistance in cancer cells
EGFR and HER2/3 are often overexpressed in chemoresistant cancer cells, promoting cell survival, proliferation, and metastasis.
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What is combined to help overcome chemoresistance in cancer cells?
Combining BMS-690514 (a dual inhibitor of EGFR and VEGFR) and cisplatin (a DNA-damaging agent) can provide a synergistic effect, overcoming chemoresistance and enhancing the efficacy of cisplatin.
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inhibiting the ___________ can sensitize tumours to chemotherapy and radiotherapy?
Inhibiting the Akt pathway (a key survival pathway in cancer cells) can sensitize tumours to chemotherapy and radiotherapy by enhancing DNA damage and apoptosis. Combining EGFR inhibitors, Akt inhibitors, and DNA alkylating agents like temozolomide can provide a synergistic effect and overcome chemoresistance.
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What is the role of Akt in protein synthesis and cell growth?
Akt promotes protein synthesis and cell growth by activating ___________ via the ____________. Akt relieves the inhibitory hold of _________ on Rheb, leading to ___________ activation and increased protein synthesis.
Akt promotes protein synthesis and cell growth by activating mTORC1 via the TSC1/2-Rheb axis. Akt relieves the inhibitory hold of TSC1/2 on Rheb, leading to mTORC1 activation and increased protein synthesis.
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What is mTOR and what are its functions 1?
mTOR is an intracellular Ser/Thr kinase that senses nutrient and energy availability as well as RTK activation. It controls cell growth, survival, and metabolism.
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What is mTOR and what are its functions 2?
mTOR is a component of two multi-protein complexes: mTORC1 and mTORC2
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What is mTOR and what are its functions 3?
mTORC1, also known as the raptor complex, is rapamycin-binding and activates global protein synthesis.
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What is mTOR and what are its functions 4?
mTORC2, also known as the rictor complex, is non-rapamycin-binding and phosphorylates Akt on Ser473.
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What is the role of mTORC1 complex in protein synthesis?
The mTORC1 complex, also known as the raptor complex, phosphorylates protein translation machinery, which leads to increased protein synthesis. One of its targets is the translational initiation factor 4E-binding protein (4E-BP1).
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What is the role of mTOR in cancer?
mTOR has a central role in protein translation, cell proliferation, and survival.
mTORC1 dysregulation may be a driving force of tumourigenesis.
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Is mTOR overexpressed in human cancer?
No, there is no described mutation/overexpression of mTOR in human cancer.
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How is mTORC1 regulated in cancer cells?
mTORC1 is regulated by signalling pathways such as PI3K, Ras/MAPK, and environmental conditions such as oxygen availability.
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What is mTORC1 addiction?
mTORC1 addiction refers to the dependence of cancer cells on the dysregulated activation of mTORC1 for their proliferation and survival.
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What is the mechanism of action of mTOR inhibitors?
They selectively block the activity of the mTORC1 complex downstream of Akt.
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Can mTOR inhibitors also block the activity of the mTORC2 complex upstream of Akt?
Yes, they may also block the activity of mTORC2.
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What is the concern with mTOR inhibition and PI3K/Akt signalling?
mTOR inhibitors may also stop natural feedback inhibition of PI3K/Akt signalling by downstream effector p70S6K.
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In what situation might there be constitutively active PI3K/Akt signalling?
In some cancers, there may be mutations or overexpression of proteins in the PI3K/Akt pathway, leading to constitutively active signalling.
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What are some mTOR inhibitors?
Some mTOR inhibitors include rapamycin (Sirolimus) and its derivatives RAD001 (Everolimus), CCI-779 (Temsirolimus), and AP23573 (Ridaforolimus).
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What other properties do mTOR inhibitors have besides inhibiting mTOR?
mTOR inhibitors are also considered anti-angiogenic, meaning they can potentially inhibit the formation of new blood vessels.
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In which type of tumors do mTOR inhibitors have potential efficacy?
mTOR inhibitors have potential efficacy in highly vascular tumor types, such as renal cell carcinoma (RCC).
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Are there ongoing clinical trials involving mTOR inhibitors in cancer patients?
Yes, there are over 150 clinical trials ongoing worldwide involving mTOR inhibitors in cancer patients.
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Have mTOR inhibitors shown promising results in the treatment of metastatic RCC?
Yes, both RAD001 and CCI-779 have been shown to lead to longer survival than standard care in the treatment of metastatic RCC. Additionally, RAD001 has even been shown to prolong survival in advanced RCC patients who were pre-treated with a VEGFR inhibitor.
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The switch from GDP to GTP is facilitated by _________
The switch from GDP to GTP is facilitated by a GEF.
