RTKS and cells signalling first lecture Flashcards
1
Q
What is signal transduction?
A
Signal transduction is the process by which a cell converts an extracellular signal into a response.
2
Q
What are the three types of chemical cell-to-cell communication?
A
Autocrine, paracrine, and endocrine.
3
Q
What is the difference between autocrine and paracrine signaling?
A
Autocrine signaling is when a cell releases a signal that acts upon itself, while paracrine signaling is when a cell releases a signal that acts upon nearby cells.
4
Q
What are the four main steps in a signal pathway?
A
Signal binds to receptor protein, activation of intracellular signal molecules, alteration of target protein, and creation of a response.
5
Q
What are some examples of signaling molecules?
A
Peptides/proteins (growth factors, vasoconstrictors), amino acid derivatives (epinephrine, histamine), other small biomolecules (ATP), steroids, prostaglandins, gases (nitric oxide), photons, damaged DNA, odorants, and tastants.
6
Q
What are the two main types of receptor locations, and what are their general characteristics?
A
Cell membrane receptors: fast response, for lipophobic ligands that can’t enter the cell (e.g. growth factor receptor).
Cytosolic/nuclear receptors: slower response, for lipophilic ligands that can enter the cell, often regulate gene expression (e.g. steroid hormone receptor).
7
Q
What are the four types of membrane receptor classes and their examples?
A
Ion channel-linked receptors (e.g. nAChR)
Receptor-enzyme linked receptors (e.g. EGFR)
G-protein coupled receptors (e.g. Angiotensin R)
Integrin receptors (e.g. Integrin αIIbβ3)
8
Q
What are the main components involved in signal transduction?
A
Membrane receptor, protein, amplifier enzymes, second messenger molecules, protein kinases, increasing intracellular calcium, phosphorylated proteins, and calcium-binding proteins.
9
Q
How do pathways amplify the signal?
A
Through enzyme cascades and signal amplification during relay, a small signal can produce a large cell response.
10
Q
What is the role of EGFR in the growth factor pathway?
A
EGFR, or epidermal growth factor receptor, is a receptor tyrosine kinase that binds to specific growth factors, leading to the activation of downstream signaling pathways such as MAPK/ERK and PI3K/Akt.
11
Q
What is the Wnt pathway?
A
The Wnt pathway is a signaling pathway involved in cell proliferation, differentiation, and migration. It plays a crucial role in embryonic development and tissue homeostasis.
12
Q
What is the Hedgehog pathway?
A
The Hedgehog pathway is a signaling pathway that regulates cell differentiation, proliferation, and tissue patterning during embryonic development and tissue repair.
13
Q
What is the Akt/mTOR pathway?
A
The Akt/mTOR pathway is a signaling pathway that regulates cell growth, proliferation, and survival. It is often dysregulated in cancer and other diseases.
14
Q
What is the Jak/Stat pathway?
A
The Jak/Stat pathway is a signaling pathway involved in immune response, cell proliferation, and differentiation. It is activated by cytokines, such as interleukins, and plays a key role in inflammation and immune regulation.
15
Q
How do cells communicate with each other during signal transduction?
A
Cells communicate with each other during signal transduction by releasing signaling molecules, which bind to specific receptors on the target cell and trigger a response.
16
Q
How do cells maintain intracellular homeostasis through signal transduction?
A
Cells maintain intracellular homeostasis through signal transduction by responding to changes in their environment and regulating various cellular processes such as nutrient uptake, energy production, and gene expression.
17
Q
How does autocrine signaling work?
A
In autocrine signaling, a cell releases signaling molecules that bind to receptors on its own surface, triggering a response within the same cell.
18
Q
How does paracrine signaling work?
A
In paracrine signaling, a cell releases signaling molecules that diffuse through the extracellular space and bind to receptors on nearby cells, triggering a response in the target cells.
19
Q
How does endocrine signaling work?
A
In endocrine signaling, a cell releases signaling molecules (hormones) into the bloodstream, which are then transported to distant target cells, where they bind to specific receptors and trigger a response.
20
Q
What happens when a signal molecule binds to a receptor protein?
A
When a signal molecule binds to a receptor protein, it triggers a conformational change in the receptor, which activates intracellular signal molecules.
21
Q
How do intracellular signal molecules alter target proteins?
A
Intracellular signal molecules can alter target proteins by adding or removing phosphate groups, binding to specific domains, or promoting conformational changes, which ultimately modulate their activity.
22
Q
How do peptides/proteins function as signaling molecules?
A
Peptides/proteins, such as growth factors and vasoconstrictors, can bind to specific receptors on target cells, initiating signal transduction pathways that regulate various cellular processes
23
Q
What are the roles of amino acid derivatives as signaling molecules?
A
Amino acid derivatives, such as epinephrine and histamine, function as signaling molecules by binding to specific receptors on target cells, modulating cellular responses like inflammation, vasodilation, or the fight-or-flight response.
24
Q
How do steroids function as signaling molecules?
A
Steroids are lipophilic molecules that can pass through the cell membrane and bind to intracellular or nuclear receptors. Upon binding, they can modulate gene expression and regulate various cellular processes, such as growth, development, and metabolism.
25
What is the role of prostaglandins as signaling molecules?
Prostaglandins are lipid-derived signaling molecules that play crucial roles in various physiological processes, including inflammation, vasodilation, blood clotting, and pain perception. They exert their effects by binding to specific membrane-bound receptors on target cells.
26
How do gases like nitric oxide function as signaling molecules?
Gases like nitric oxide can function as signaling molecules by diffusing across cell membranes and directly interacting with intracellular target proteins, such as soluble guanylyl cyclase, which modulates cGMP levels and triggers a cellular response.
27
What is the difference between lipophobic and lipophilic ligands?
Lipophobic ligands are water-soluble and cannot pass through the cell membrane, while lipophilic ligands are fat-soluble and can easily diffuse through the membrane.
28
How do fast-response membrane receptors work?
Fast-response membrane receptors, like ion channels or receptor-enzyme linked receptors, initiate rapid cellular responses upon ligand binding by changing their conformation or activating intracellular enzymes.
29
How do slower-response cytosolic/nuclear receptors work?
Slower-response cytosolic/nuclear receptors, like steroid hormone receptors, regulate gene expression by binding to lipophilic ligands that enter the cell, forming a complex that translocates to the nucleus and interacts with specific DNA sequences.
30
How do ion channel-linked receptors function?
Ion channel-linked receptors function by undergoing a conformational change upon ligand binding, opening or closing an ion channel that allows ions to pass through the cell membrane, thus altering the membrane potential and causing a cellular response.
31
How do receptor-enzyme linked receptors function?
Receptor-enzyme linked receptors function by activating an intracellular enzyme upon ligand binding, triggering a downstream cascade of signaling events that lead to a cellular response.
32
How do G-protein coupled receptors function?
G-protein coupled receptors function by activating an intracellular G protein upon ligand binding, which then interacts with other signaling molecules, such as enzymes or ion channels, to modulate cellular responses.
33
How do integrin receptors function?
Integrin receptors function by binding to extracellular matrix components and interacting with intracellular proteins, such as the actin cytoskeleton, to modulate cellular adhesion, migration, and signaling.
34
What are amplifier enzymes and how do they function in signal transduction?
Amplifier enzymes are intracellular enzymes that catalyze the production of multiple second messenger molecules upon activation by a signaling pathway. They amplify the signal by rapidly increasing the concentration of second messengers inside the cell.
35
What is the role of protein kinases in signal transduction?
Protein kinases are enzymes that phosphorylate target proteins in response to signaling events, which can activate or deactivate the target proteins, modulating their function and ultimately leading to a cellular response.
36
How does increasing intracellular calcium contribute to signal transduction?
Increasing intracellular calcium levels can activate calcium-binding proteins, such as calmodulin, which in turn can modulate the activity of various target proteins, including ion channels, enzymes, and transcription factors, ultimately leading to a cellular response.
37
What is an enzyme cascade?
An enzyme cascade is a series of sequential reactions involving enzymes, where the product of one reaction serves as the substrate for the next reaction. This cascade effect can amplify a signal, leading to a larger cellular response.
38
How does signal amplification occur during relay in signal transduction pathways?
Signal amplification during relay occurs when each signaling molecule in the pathway activates multiple downstream molecules, creating a cascade effect that leads to a large cellular response from a small initial signal.
39
What is the purpose of signal amplification in cell signaling?
Signal amplification in cell signaling ensures that a small extracellular signal, such as the binding of a single ligand to a receptor, can produce a robust and coordinated cellular response by activating multiple intracellular signaling molecules and pathways.
40
What are proto-oncogenes?
Proto-oncogenes are normal genes that, when mutated or overexpressed, can contribute to the development of cancer. They play a role in regulating cell growth, differentiation, and survival.
41
How can signaling proteins contribute to cancer development?
Signaling proteins can contribute to cancer development when mutations or dysregulation in their function lead to uncontrolled cell growth, survival, or proliferation, resulting in tumor formation.
42
What are serine/threonine kinases?
Serine/threonine kinases are enzymes that phosphorylate serine and threonine residues on target proteins, playing a role in regulating various cellular processes, including signal transduction, cell division, and apoptosis.
43
What is the role of Raf kinases in cell signaling?
Raf kinases are serine/threonine kinases that play a crucial role in the MAPK/ERK signaling pathway, which regulates cell growth, differentiation, and survival.
44
What are non-receptor tyrosine kinases?
Non-receptor tyrosine kinases are intracellular enzymes that phosphorylate tyrosine residues on target proteins, playing a role in various signaling pathways that regulate cell growth, survival, and differentiation.
45
What is the role of Src kinases in cell signaling?
Src kinases are non-receptor tyrosine kinases that regulate various cellular processes, including cell adhesion, migration, and proliferation. They are involved in multiple signaling pathways and have been implicated in cancer development.
46
What is the role of Abl kinases in cell signaling?
Abl kinases are non-receptor tyrosine kinases that play a role in regulating cell growth, survival, and differentiation. They have been implicated in the development of certain types of leukemia, such as chronic myeloid leukemia (CML).
47
What are GTP-binding proteins?
GTP-binding proteins, also known as G-proteins, are intracellular signaling molecules that bind to guanosine triphosphate (GTP) and play a role in various signal transduction pathways, including those involved in cell growth, survival, and differentiation.
48
What is the role of Ras proteins in cell signaling?
Ras proteins are small GTP-binding proteins that function as molecular switches in various signaling pathways, including the MAPK/ERK and PI3K/Akt pathways. Mutations in Ras genes are frequently found in human cancers, contributing to uncontrolled cell growth and survival.
49
___________is a protein that stimulates cell growth, proliferation, and differentiation by binding to its receptor, It plays a crucial role in processes such as wound healing and tissue repair.
Epidermal Growth Factor (EGF)
50
___________is a family of growth factors involved in various biological processes, including cell growth, development, wound healing, and angiogenesis. it exerts their effects by binding to __________ receptors, which are receptor tyrosine kinases.
Fibroblast Growth Factor (FGF) and FGF
51
________is a growth factor that plays a key role in angiogenesis, the formation of new blood vessels from pre-existing ones. __________promotes endothelial cell proliferation, migration, and survival by binding to ___________ receptors.
Vascular Endothelial Growth Factor (VEGF)
52
______________is a growth factor that stimulates cell growth and division, particularly in connective tissue cells such as fibroblasts, smooth muscle cells, and glial cells. ____________ is released from platelets during blood clotting and plays a role in wound healing and tissue repair.
Platelet-Derived Growth Factor (PDGF)
53
_______________ is a family of growth factors that regulate a wide range of cellular processes, including cell growth, differentiation, apoptosis, and extracellular matrix production. _________ can have both tumor-suppressive and tumor-promoting effects, depending on the cellular context.
Transforming Growth Factor-beta (TGF-β)
54
___________ is a growth factor involved in various cellular processes, including cell adhesion, migration, proliferation, angiogenesis, and extracellular matrix production. It is particularly important for the development and maintenance of connective tissues, such as cartilage, bone, and fibrous tissue. ____________ has also been implicated in the progression of fibrosis and tumor growth.
Connective Tissue Growth Factor (CTGF)
55
__________is a family of growth factors, including __ and ______, that share structural similarities with insulin. _________ play crucial roles in cell growth, proliferation, differentiation, and survival. They exert their effects by binding to _________receptors, which are receptor tyrosine kinases. _________are also involved in metabolic regulation and have been implicated in aging and various diseases, such as cancer and diabetes.
IGF is a family of growth factors, including IGF-1 and IGF-2, that share structural similarities with insulin. IGFs play crucial roles in cell growth, proliferation, differentiation, and survival. They exert their effects by binding to IGF receptors, which are receptor tyrosine kinases. IGFs are also involved in metabolic regulation and have been implicated in aging and various diseases, such as cancer and diabetes.
56
____________also known as FGF-7, is a member of the fibroblast growth factor (FGF) family. __________ is primarily produced by cells in the dermis and stimulates the growth, migration, and differentiation of keratinocytes, the predominant cell type in the epidermis. ________plays a vital role in skin development, wound healing, and the maintenance of the skin barrier.
KGF, also known as FGF-7, is a member of the fibroblast growth factor (FGF) family. KGF is primarily produced by cells in the dermis and stimulates the growth, migration, and differentiation of keratinocytes, the predominant cell type in the epidermis. KGF plays a vital role in skin development, wound healing, and the maintenance of the skin barrier.
57
What are oncogenic retroviruses?
Oncogenic retroviruses are RNA viruses that can cause cancer by integrating their viral genome into the host cell DNA, resulting in the activation of oncogenes or the disruption of tumor suppressor genes.
58
What is a viral oncogene tyrosine kinase (TK)?
Viral oncogene tyrosine kinases are protein kinases encoded by oncogenic retroviruses that can phosphorylate tyrosine residues on target proteins, leading to the activation of signaling pathways that promote cell growth, survival, and transformation.
59
How do oncogenic retroviruses activate tyrosine kinases?
Oncogenic retroviruses can activate tyrosine kinases by encoding truncated versions of receptor tyrosine kinases (RTKs) that lack regulatory domains. This results in the removal of inhibitory influences on the intracellular tyrosine kinase domain, leading to constitutive activation of the kinase and downstream signaling pathways
60
What is v-erbB, and how does it contribute to oncogenesis?
V-erbB is a viral oncogene derived from the avian erythroblastosis virus (AEV) that encodes a truncated version of the epidermal growth factor receptor (EGFR). It lacks the C-terminal tyrosine kinase regulatory domain, resulting in the constitutive activation of EGFR without the need for ligand binding. This aberrant activation of EGFR promotes uncontrolled cell growth and survival, contributing to oncogenesis.
61
What is the significance of understanding viral oncogene TK activation in cancer research?
Understanding viral oncogene TK activation helps researchers identify the molecular mechanisms underlying cancer development and progression. This knowledge can aid in the development of targeted therapies that specifically inhibit the activity of aberrantly activated tyrosine kinases, potentially leading to more effective cancer treatments.
62
____________is a post-translational modification process in which a phosphate group is added to a specific amino acid residue (usually serine, threonine, or tyrosine) on a target protein. This process is catalyzed by enzymes called kinases.
Phosphorylation is a post-translational modification process in which a phosphate group is added to a specific amino acid residue (usually serine, threonine, or tyrosine) on a target protein. This process is catalyzed by enzymes called kinases.
63
What are the roles of phosphorylation in cellular processes?
Phosphorylation plays a crucial role in regulating various cellular processes, including protein function, enzyme activity, protein-protein interactions, cellular localization, and protein stability. Phosphorylation can either activate or inhibit the function of target proteins, depending on the specific residue and protein being modified.
64
In signal transduction pathways, phosphorylation is a key mechanism for transmitting extracellular signals into intracellular responses. The binding of a ligand to a cell surface receptor (such as a receptor tyrosine kinase) can trigger a series of _____________ events, which activate or deactivate target proteins and ultimately lead to changes in ___________ or _____________
In signal transduction pathways, phosphorylation is a key mechanism for transmitting extracellular signals into intracellular responses. The binding of a ligand to a cell surface receptor (such as a receptor tyrosine kinase) can trigger a series of phosphorylation events, which activate or deactivate target proteins and ultimately lead to changes in cellular function or gene expression.
65
_______________ are enzymes that catalyze the transfer of a phosphate group from ATP to a target protein, while _____________ are enzymes that remove phosphate groups from phosphorylated proteins. The balanced activities of ___________ and ______________ are essential for maintaining proper cellular function and ________________________
Kinases are enzymes that catalyze the transfer of a phosphate group from ATP to a target protein, while phosphatases are enzymes that remove phosphate groups from phosphorylated proteins. The balanced activities of kinases and phosphatases are essential for maintaining proper cellular function and ensuring that signal transduction pathways are tightly regulated.
66
Dysregulation of phosphorylation can lead to the ____________________, such as cell growth, survival, and differentiation. This can contribute to the development and progression of various diseases, including cancer, neurodegenerative disorders, and autoimmune diseases. Understanding the role of phosphorylation in these diseases can help identify ___________________
Dysregulation of phosphorylation can lead to the aberrant activation or inactivation of proteins involved in essential cellular processes, such as cell growth, survival, and differentiation. This can contribute to the development and progression of various diseases, including cancer, neurodegenerative disorders, and autoimmune diseases. Understanding the role of phosphorylation in these diseases can help identify potential therapeutic targets for their treatment.
67
What are protein kinases and how do they function in phosphorylation?
Protein kinases are enzymes that transfer the terminal phosphate group of ATP to a hydroxyl group on a target protein. This process acts as a positive switch, often activating or altering the function of the target protein.
68
What are protein phosphatases and how do they function in phosphorylation?
Protein phosphatases are enzymes that catalyze the removal of phosphate groups from phosphorylated proteins through hydrolysis. This process acts as a negative switch, often inactivating or returning the target protein to its original state.
69
How does the balance between protein kinases and protein phosphatases regulate cellular processes?
The balance between the activities of protein kinases and protein phosphatases ensures that ___________________. Imbalances in kinase or phosphatase activity can lead to _____________________
The balance between the activities of protein kinases and protein phosphatases ensures that proteins are correctly modified and that cellular processes are tightly regulated. Imbalances in kinase or phosphatase activity can lead to dysregulation of cellular processes and contribute to the development of diseases.
70
What is the importance of phosphorylation in signaling pathways?
Phosphorylation is a critical mechanism for ______________ within cells. It allows for _____________ in response to extracellular signals or changes in the cellular environment. Proper regulation of phosphorylation is essential for maintaining cellular homeostasis and ________________
Phosphorylation is a critical mechanism for transmitting and modulating signals within cells. It allows for rapid and reversible regulation of protein function in response to extracellular signals or changes in the cellular environment. Proper regulation of phosphorylation is essential for maintaining cellular homeostasis and coordinating various cellular processes.
71
COMPLETE THE MISSING STUFF AND WORK OUT WHAT THE REACTION WILL GIVE BASED ON YOU KNOWLEGDE
72
What is the general mechanism of RTK activation?
Receptor tyrosine kinases (RTKs) are activated through ____________, a process in which two RTK monomers come together to form a dimer. This ____________ then triggers ___________________, initiating downstream signaling pathways.
Receptor tyrosine kinases (RTKs) are activated through dimerization, a process in which two RTK monomers come together to form a dimer. This dimerization then triggers the phosphorylation of tyrosine residues on the intracellular domains of the receptors, initiating downstream signaling pathways.
73
How do pre-dimerized and dimer-on-activation RTKs differ in activation?
Some RTKs, like ________ and __________ receptors, are already present as dimers in their inactive state. Upon ligand binding, they undergo a conformational change that _____________ In contrast, other RTKs, such as EGFR, exist as _____________ in their inactive state and form dimers upon __________ and _____________.
Some RTKs, like insulin and PDGF receptors, are already present as dimers in their inactive state. Upon ligand binding, they undergo a conformational change that activates their kinase domains. In contrast, other RTKs, such as EGFR, exist as monomers in their inactive state and form dimers upon ligand binding and activation.
74
What is an alternative mechanism for RTK activation?
Apart from ligand-induced dimerization, some RTKs can also be activated by ________________, such as Src. This phosphorylation can lead to the activation of the RTK and the initiation of downstream _________________.
Apart from ligand-induced dimerization, some RTKs can also be activated by phosphorylation of their intracellular domains by non-receptor tyrosine kinases, such as Src. This phosphorylation can lead to the activation of the RTK and the initiation of downstream signaling pathways.
75
Why is understanding RTK activation mechanisms important in biomedical research?
RTKs play crucial roles in many cellular processes, such as cell growth, differentiation, and survival. Dysregulation of RTK signaling can contribute to the development of various diseases, including cancer. Understanding the different mechanisms of RTK activation can help identify potential therapeutic targets and strategies for treating these diseases.
76
How can targeting RTK activation mechanisms be used in therapeutic strategies?
By understanding the specific activation mechanisms of different RTKs, researchers can develop targeted therapies that either _________, __________, or _____________. These targeted therapies can help disrupt aberrant RTK signaling and potentially provide more effective treatments for diseases like cancer.
By understanding the specific activation mechanisms of different RTKs, researchers can develop targeted therapies that either block ligand binding, prevent dimerization, or inhibit kinase activity. These targeted therapies can help disrupt aberrant RTK signaling and potentially provide more effective treatments for diseases like cancer.
77
What is the significance of EGFR (ErbB1) in the history of RTK research?
EGFR, also known as ErbB1, was the first receptor tyrosine kinase to be cloned in 1984. Its discovery has paved the way for further research into RTKs and their roles in various cellular processes and diseases.
78
What are the other members of the EGFR family?
The EGFR family consists of four members: EGFR/ErbB1, HER2/ErbB2, HER3/ErbB3, and HER4/ErbB4. These receptors are often co-expressed in various combinations and can form different homo- or heterodimers.
79
How do HER2 and HER3 differ from other EGFR family members?
HER2 and HER3 are ____________. HER2 has an extracellular domain that is constitutively locked in ___________, which means it does not require a ligand for activation and is always ready for dimerization. HER3 has _______________ and must form heterodimers with other EGFR family members to gain activity.
HER2 and HER3 are functionally incomplete. HER2 has an extracellular domain that is constitutively locked in an active conformation, which means it does not require a ligand for activation and is always ready for dimerization. HER3 has an inactive catalytic domain and must form heterodimers with other EGFR family members to gain activity.
80
Which growth factors activate the EGFR family members?
EGFR family members can be activated by a large group of EGF-related growth factors, including EGF, TGFα, epiregulin, betacellulin, heparin-binding EGF-like growth factor, amphiregulin, and neuregulins.
81
Why is understanding the EGFR family important in biomedical research and cancer therapy?
EGFR family members play crucial roles in cell growth, differentiation, and survival. Dysregulation of EGFR signaling is implicated in various diseases, including cancer. Understanding the EGFR family and its activation mechanisms can help develop targeted therapies to __________________________
EGFR family members play crucial roles in cell growth, differentiation, and survival. Dysregulation of EGFR signaling is implicated in various diseases, including cancer. Understanding the EGFR family and its activation mechanisms can help develop targeted therapies to inhibit aberrant signaling and provide more effective treatments for diseases like cancer.
82
What is the role of tyrosine phosphorylation in RTK activation?
Tyrosine phosphorylation is a key step in the activation of receptor tyrosine kinases (RTKs). Upon ligand binding, the RTKs undergo ________________on specific tyrosine residues between the two subunits, which enhances their kinase activity and initiates downstream signaling pathways.
Tyrosine phosphorylation is a key step in the activation of receptor tyrosine kinases (RTKs). Upon ligand binding, the RTKs undergo autophosphorylation (transphosphorylation) on specific tyrosine residues between the two subunits, which enhances their kinase activity and initiates downstream signaling pathways.
83
How does ligand binding lead to autophosphorylation in RTKs?
Ligand binding to the extracellular domain of an RTK induces a conformational change, promoting dimerization of the receptor. This dimerization brings the intracellular kinase domains of the two subunits into close proximity, allowing them to phosphorylate each other's tyrosine residues in a process known as transphosphorylation or autophosphorylation.
84
What is the function of autophosphorylation in RTK activation?
Autophosphorylation has two main functions in RTK activation: (1) enhancing the catalytic activity of the kinase domain, which allows for the phosphorylation of downstream signaling proteins, and (2) exposing docking sites for SH2 (src homology 2) domain-containing proteins, which serve as adaptor proteins to recruit and activate additional signaling molecules.
85
What are SH2 domains, and why are they important for RTK signaling?
SH2 domains are protein domains that specifically recognize and bind to phosphorylated tyrosine residues on target proteins. In the context of RTK signaling, SH2 domain-containing proteins are recruited to the phosphorylated tyrosines on activated RTKs, which helps assemble signaling complexes and propagate the signal downstream.
86
How does the activation of RTKs by tyrosine phosphorylation contribute to the regulation of cellular processes?
RTK activation through tyrosine phosphorylation triggers a cascade of intracellular signaling events, which can regulate various cellular processes, such as cell growth, differentiation, migration, and survival. Dysregulation of RTK activation can contribute to the development of diseases, including cancer, making RTKs potential therapeutic targets.
87
What is the role of tyrosine phosphorylation as a post-translational modification in RTK activation?
Tyrosine phosphorylation serves as a molecular "switch" that activates receptor tyrosine kinases (RTKs) and triggers a conformational change in the protein, turning it "on" or "off". This post-translational modification is essential for proper signal transduction and regulation of various cellular processes.
88
How does the conformational change induced by tyrosine phosphorylation affect RTK activity?
The conformational change induced by tyrosine phosphorylation promotes the dimerization and activation of the RTKs, enhances the kinase activity of the intracellular domain, and exposes docking sites for SH2 domain-containing proteins. This ultimately enables signal transduction and the activation of downstream signaling pathways.
89
What are the two main ways that signal transduction occurs following RTK activation by tyrosine phosphorylation?
Signal transduction after RTK activation can occur through: (1) direct tyrosine phosphorylation of other proteins by the activated RTK, or (2) the formation of complexes with other proteins, such as those containing SH2 domains, which serve as docking sites for the recruitment and activation of additional signaling molecules.
90
Why is the regulation of RTK activation by tyrosine phosphorylation important for cellular function?
Proper regulation of RTK activation by tyrosine phosphorylation is crucial for maintaining the balance of cellular processes such as growth, differentiation, migration, and survival. Dysregulation of this signaling mechanism can contribute to the development of diseases, including cancer.
91
How can understanding the role of tyrosine phosphorylation in RTK activation inform therapeutic strategies?
By understanding the molecular mechanisms underlying RTK activation through tyrosine phosphorylation, researchers can develop targeted therapies that either inhibit or modulate RTK signaling in diseases where it is dysregulated, such as cancer or other signaling-related disorders.
92
How are RTKs activated?
RTK activation occurs when a specific ligand binds to the extracellular domain of the receptor, inducing a conformational change that promotes dimerization (or oligomerization) of the receptor. This dimerization brings the intracellular kinase domains of the two subunits into close proximity, allowing them to phosphorylate each other's tyrosine residues in a process known as transphosphorylation or autophosphorylation.
93
What happens after RTK activation?
Following RTK activation, several intracellular signaling pathways are triggered, such as the MAPK/ERK pathway, the PI3K/Akt pathway, and the PLCγ/PKC pathway. These pathways ultimately regulate gene expression and various cellular processes, including cell growth, survival, migration, and differentiation.
94
Why is the regulation of RTK activation important?
Proper regulation of RTK activation is essential for maintaining the balance of cellular processes and preventing the development of diseases, including cancer. Dysregulation of RTK signaling can lead to uncontrolled cell growth and other cellular abnormalities. Understanding RTK activation mechanisms can inform the development of targeted therapies for diseases caused by dysregulated RTK signaling.
95
COMPLETE THE IMAGE AND WHAT IS IT ABOUT?
96
WHAT DOEES EACH MIDLE ICON DO?
97
WHAT DOES EACH LINE BIND TO? COMP;LETE THE IMAGE
98
EXPLAINING THIS IMAGE
What is the general concept depicted in the image
illustrates the binding of docking proteins to the intracellular domain of the platelet-derived growth factor (PDGF) receptor following its activation. The image shows specific tyrosine kinase domains, the SH2 and SH3 domains, and the recruitment of signaling molecules such as PI-3 kinase regulatory subunit, GTPase-activating protein (GAP), and phospholipase C-gamma (PLCγ).
99
How does the binding of docking proteins to RTKs occur?
The binding of docking proteins to RTKs, such as the PDGF receptor, is sequence-specific and occurs via interactions between the SH2 domains of the docking proteins and the phosphorylated tyrosine residues on the activated RTK. This interaction enables the recruitment and activation of downstream signaling molecules.
100
What is the role of SH2 and SH3 domains in RTK signaling?
SH2 and SH3 domains are found in many signaling proteins and serve as interaction modules that help facilitate the assembly of signaling complexes. SH2 domains specifically recognize and bind to phosphorylated tyrosine residues on activated RTKs, while SH3 domains typically bind to proline-rich sequences in target proteins.
101
What are the functions of the PI-3 kinase regulatory subunit, GTPase-activating protein (GAP), and phospholipase C-gamma (PLCγ)?
PI-3 kinase regulatory subunit: A component of the PI3K complex that plays a role in the activation of the PI3K/Akt signaling pathway, which regulates cell growth, survival, and metabolism.
GTPase-activating protein (GAP): Regulates the activity of small GTPases, such as Ras, by promoting the conversion of active GTP-bound forms to inactive GDP-bound forms, thus modulating various cellular processes.
Phospholipase C-gamma (PLCγ): An enzyme that cleaves phospholipids to generate inositol trisphosphate (IP3) and diacylglycerol (DAG), which serve as second messengers to activate downstream signaling pathways, such as the protein kinase C (PKC) pathway.
102
Why is the sequence-specific binding of docking proteins to activated RTKs important?
Sequence-specific binding of docking proteins to activated RTKs ensures the proper recruitment and activation of downstream signaling molecules, leading to the precise regulation of cellular processes. Dysregulation of these interactions can result in aberrant signaling and contribute to the development of diseases, including cancer.
103
Why is the sequence-specific binding of docking proteins to activated RTKs important?
Sequence-specific binding of docking proteins to activated RTKs ensures the proper recruitment and activation of downstream signaling molecules, leading to the precise regulation of cellular processes. Dysregulation of these interactions can result in aberrant signaling and contribute to the development of diseases, including cancer.
104
EXPLAIN EACH TERM, WHAT THEY DO?
Non-receptor TKs such as Src?
Phospholipase Cγ (PLCγ):
Phosphatidylinositol 3’ kinase (PI 3-kinase):
SHP2 tyrosine phosphatase:
GTPase activating protein
Nck2:
Non-receptor TKs such as Src: Kinases that are not part of a receptor but still play crucial roles in various signaling pathways.
Phospholipase Cγ (PLCγ): An enzyme that breaks down phosphatidylinositol (4,5) bisphosphate (PI4,5P2) into second messengers IP3 and DAG.
Phosphatidylinositol 3’ kinase (PI 3-kinase): An enzyme that phosphorylates PI4,5P2 to generate the second messenger PI3,4,5P3.
SHP2 tyrosine phosphatase: An enzyme that dephosphorylates phosphorylated tyrosine residues on RTKs.
GTPase activating protein: A protein that inactivates p21Ras-GTP, thus modulating small GTPase activity.
Nck2: A protein involved in the regulation of the cytoskeleton.
105
What is the purpose of attenuation and termination in the context of RTK activation?
Attenuation and termination help in stopping or reducing the intensity of RTK activation, thus maintaining cellular balance and preventing excessive signaling.
106
What is ligand displacement, and how does it contribute to the regulation of RTK activation?
Ligand displacement is the process where one ligand is replaced by another, potentially modulating receptor activation. It can change the signaling outcome by altering the strength or duration of RTK activation.
107
How do endocytosis and degradation contribute to the termination of RTK signaling?
Endocytosis and degradation involve the internalization and breakdown of receptors by the cell, effectively terminating the signal by removing the receptor from the cell membrane and preventing further signaling.
108
What is the role of Protein Tyrosine Phosphatases (PTP) in the regulation of RTK activation?
PTPs are enzymes that remove phosphate groups from phosphorylated tyrosine residues, reversing the activation of RTKs and contributing to the termination of signaling.
109
How does Protein Kinase C (PKC) help regulate RTK activation?
PKC is a family of enzymes that play a role in the regulation of various cellular processes, including the termination of RTK activation. They can modulate signaling pathways downstream of RTKs, thus influencing the overall cellular response.
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What are ligand antagonists and how do they contribute to attenuation and termination of RTK activation?
Ligand antagonists are molecules that bind to a receptor but do not activate it. They compete with the actual ligands for the binding site, thereby preventing receptor activation and contributing to attenuation and termination of RTK signaling.
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How do receptor antagonists help in the attenuation and termination of RTK activation?
Receptor antagonists are molecules that bind to receptors and inhibit their activation, either by blocking the ligand-binding site or by interfering with receptor dimerization or conformational changes. They help in attenuation and termination of RTK activation by preventing the receptor from sending signals downstream.
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How do phosphorylation and dephosphorylation contribute to the attenuation and termination of RTK activation?
Phosphorylation and dephosphorylation are key regulatory mechanisms for RTK activation. Phosphorylation activates the receptor, while dephosphorylation, mediated by protein tyrosine phosphatases (PTPs), reverses the activation, contributing to attenuation and termination of signaling.
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How does receptor endocytosis contribute to the attenuation and termination of RTK activation?
Receptor endocytosis involves the internalization of the receptor from the cell membrane into intracellular vesicles. This process removes the receptor from the cell surface, reducing its availability for ligand binding and subsequent signaling, thus contributing to the attenuation and termination of RTK activation.
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How does the ubiquitin-proteasome pathway contribute to the attenuation and termination of RTK activation?
The ubiquitin-proteasome pathway is a mechanism for protein degradation, where proteins are tagged with ubiquitin molecules and targeted for degradation by the proteasome complex. Receptor degradation through this pathway helps to reduce the number of active receptors on the cell surface, thus contributing to attenuation and termination of RTK signaling.
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DRAW OUT EACH STRUCTURE
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What are tyrosine kinase inhibitors (TKIs)?
Low molecular weight compounds used to inhibit tyrosine kinases, which are enzymes involved in the regulation of various cellular processes, including cell growth and proliferation.
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What are the difficulties associated with targeting tyrosine kinases using low molecular weight compounds?
Low molecular weight compounds may have difficulty interfering with ligand binding or protein substrate, and approaches to generate non-competitive or allosteric inhibitors have also failed.
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What is the target of choice for tyrosine kinase inhibition?
The ATP binding site in tyrosine kinases.
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What are the key interactions between ATP and tyrosine kinases?
Two key hydrogen bonds are formed between the adenine ring of ATP and the N-1 and N-6 amino groups.
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How can the hydrophobic pocket in tyrosine kinases be exploited for inhibitor selectivity?
The hydrophobic pocket can play an important role in inhibitor selectivity by allowing for the targeting of specific tyrosine kinases.
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What are the cellular targets of tyrosine kinase inhibitors?
Tumor cells, endothelial cells in tumor angiogenesis (VEGFRs), and stromal fibroblasts.
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What is structure-based drug design?
Structure-based drug design uses crystallographic structure information to develop new drugs.
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What is combinatorial chemistry and high-throughput screening?
Combinatorial chemistry and high-throughput screening are methods used to rapidly generate and screen large numbers of drug candidates.
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What is the goal of tyrosine kinase inhibitor development?
The goal of tyrosine kinase inhibitor development is to achieve greater potency, greater selectivity, higher efficacy, decreased toxicity, and better absorption, distribution, metabolism, and excretion (ADMET).
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What is the mechanism of action of tyrosine kinase inhibitors?
Tyrosine kinase inhibitors bind specifically to the kinase domain of tyrosine kinases and block substrate phosphorylation and subsequent downstream signaling.
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What is v-erbB, and how does it contribute to oncogenesis?
V-erbB is a viral oncogene derived from the avian erythroblastosis virus (AEV) that encodes a truncated version of the epidermal growth factor receptor (EGFR). It lacks the C-terminal tyrosine kinase regulatory domain, resulting in the constitutive activation of EGFR without the need for ligand binding. This aberrant activation of EGFR promotes uncontrolled cell growth and survival, contributing to oncogenesis.
