3 intracellular signalling. Flashcards
What are the pathways that lead to cell growth and survival upon RTK activation?
The Akt pathway and MAP kinase pathway are the two main pathways that lead to cell growth and survival upon RTK activation.
How can different receptor homo- or heterodimers affect activation pathways?
Different receptor homo- or heterodimers can have different propensities to activate various arms of activation pathways
What is the significance of overactivity of TK signaling cascades?
As TK signaling cascades are often mitogenic, their overactivity is of great interest for the treatment of cancers.
What is the full form of RTK?
RTK stands for Receptor Tyrosine Kinase.
What is the full form of TK?
TK stands for Tyrosine Kinase.
What is the main downstream effector of the Akt pathway?
The main downstream effector of the Akt pathway is mTORC1.
What is the full form of MAP kinase?
MAP kinase stands for Mitogen-Activated Protein Kinase.
What are the three main components of the MAP kinase pathway?
The three main components of the MAP kinase pathway are Ras, Raf, and ERK.
What is the function of Ras in the MAP kinase pathway?
Ras acts as a molecular switch that is turned on by activated RTKs, which in turn activates downstream effectors including the MAP kinase pathway.
What are the different types of receptor dimers?
Receptor dimers can be homo- or heterodimers. Homo- dimers consist of two identical receptor subunits, while heterodimers consist of two different subunits.
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What is the canonical MAPK pathway?
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).
What is the first step in the canonical MAPK pathway?
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).
What is the role of Raf in the canonical MAPK pathway?
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).
What is the role of MEK in the canonical MAPK pathway?
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).
What are the three main MAPKs in the canonical MAPK pathway?
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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)
What is the final outcome of the canonical MAPK pathway?
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.
What are the different types of signals that can activate MAPK pathways?
MAPK pathways can be activated by a wide variety of signals, including growth factors, cytokines, stress signals, and environmental cues.
How does the activation of MAPK pathways by multiple signals lead to specificity?
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.
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How is Ras activated by RTK?
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.
What is the role of Ras in signal transduction pathways?
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.
What is the structure of Ras?
Ras is 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.
What is the difference between active and inactive forms of Ras?
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.
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.
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.
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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.
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
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.
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.
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.
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.
Function of the Ras protein
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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.
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.
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.
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.
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.
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).
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.
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).
What is the role of MAPKKs in the MAPK signal cascade?
MAPKKs phosphorylate and activate the third class of kinase called MAPKs.
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.
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.
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.
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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.
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.
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.
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).
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.
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.
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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.
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.
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.
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.
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.
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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.
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.
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.
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.
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.
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.
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.
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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).
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.
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).
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.
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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.
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.
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.
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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.
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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.
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.
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.
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.
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.
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.
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 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.
What is mTOR and what are its functions 2?
mTOR is a component of two multi-protein complexes: mTORC1 and mTORC2
What is mTOR and what are its functions 3?
mTORC1, also known as the raptor complex, is rapamycin-binding and activates global protein synthesis.
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.
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).
The switch from GDP to GTP is facilitated by _________
The switch from GDP to GTP is facilitated by a GEF.
