Problem Set 11

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Questions and Answers

Which molecule is primarily responsible for activating the monomeric G protein Ras in receptor tyrosine kinase signaling?

Ras-Gβγ

Ras-Gα

Ras-GEF (correct)

Ras-GAP

Which cytoplasmic tyrosine kinase is associated with integrins at cell-extracellular matrix junctions?

Rho

Src

FAK (correct)

STAT

What type of mutation in the regulatory subunit of PKA would likely lead to a permanently active enzyme?

Mutations that reduce binding affinity for cyclic AMP

Mutations that prevent binding to catalytic subunits (correct)

Mutations that enhance binding to cyclic AMP

Mutations that stabilize the inactive conformation

Ryanodine and IP3 receptors are localized on which type of membrane?

Endoplasmic reticulum membranes Signup and view all the answers

Following the binding of interleukin-2 to its receptor on T lymphocytes, which process is triggered?

Increase in phosphotyrosine levels Signup and view all the answers

Which of the following are considered phosphoinositide-derived messengers?

DAG and IP3 Signup and view all the answers

Why can each RTK activate diverse downstream pathways?

Phosphorylated tyrosine residues interact with various adaptor proteins Signup and view all the answers

What mechanism does L-Arginine use to promote vasodilation for cardiac health?

It serves as a substrate for nitric oxide production Signup and view all the answers

What effect does NO have on smooth muscle cells in arteries?

It causes the cells to relax, leading to vasodilation. Signup and view all the answers

What happens to Ras activity in the absence of extracellular signals if Ras-specific GAP activity is lacking?

There is sustained signaling due to increased GTP-bound Ras. Signup and view all the answers

If a mutant RTK lacks an extracellular domain, what is the expected outcome?

The RTK cannot bind ligands, making it inactive. Signup and view all the answers

What is required to turn off signaling in a cell line with a constitutively active Ras protein?

Addition of a drug that blocks protein Y from interacting with its target. Signup and view all the answers

What occurs when insulin binds to the insulin receptor (IR)?

IRS-1 binds to the activated insulin receptor. Signup and view all the answers

How does MEK influence Ras-specific GEF and GAP activities?

It activates GEF providing positive feedback, while GAP activation gives negative feedback. Signup and view all the answers

What mutation could potentially increase proliferation in cultured chicken cells when the growth factor SuperX binds an RTK?

A mutation that promotes the active dimer state of the RTK. Signup and view all the answers

What is the expected outcome when insulin binds to its receptor on an adipocyte?

Tyr phosphorylation of the docking protein IRS Signup and view all the answers

What effect do mutations in RAS genes at specific codons have on signaling pathways downstream of RAS?

Downstream pathways would be constitutively activated Signup and view all the answers

If a cell-surface receptor has intrinsic enzymatic activity, it is classified as a _____.

Catalytic receptor Signup and view all the answers

Which property is unique to the process of GPCR signal termination?

Binding to arrestins Signup and view all the answers

What enzyme does lithium inhibit in relation to the production of IP3 and DAG?

Phospholipase C activity Signup and view all the answers

What best describes a receptor that is activated by ligand binding and adds phosphates from ATP to tyrosine side chains in its own cytoplasmic domain?

Receptor tyrosine kinase (RTK) Signup and view all the answers

What distinguishes the activity of phosphoinositide 3-kinase (PI3-kinase)?

Phosphorylates inositol phospholipids upon receptor activation Signup and view all the answers

What receptor type is prevented from engaging in endocytosis when an antibody binds its extracellular domain?

Receptor tyrosine kinase Signup and view all the answers

What is likely to happen to downstream pathways when mutations in RAS genes prevent RAS-GTP hydrolysis?

Downstream pathways would be constantly activated. Signup and view all the answers

How is an RTK expected to respond when an antibody binds to its extracellular domain?

The binding will lead to receptor activation. Signup and view all the answers

What function does lithium fulfill in the context of IP3 and DAG production?

It inhibits the function of phospholipase C. Signup and view all the answers

Which type of receptor is characterized by the capability of adding phosphates to tyrosine side chains in its cytoplasmic domain?

Receptor tyrosine kinase Signup and view all the answers

In which mechanism does receptor phosphorylation play a key role during GPCR signal termination?

Binding to arrestins Signup and view all the answers

Which receptor type is classified as having intrinsic enzymatic activity?

Receptor tyrosine kinase Signup and view all the answers

What role does phosphoinositide 3-kinase (PI3-kinase) serve after receptor activation?

It phosphorylates inositol phospholipids. Signup and view all the answers

Which signaling effect is associated with insulin binding to its receptor in adipocytes?

Phosphorylation of IRS docking proteins Signup and view all the answers

What effect does the lack of Ras-specific GAP activity have on Ras signaling?

Ras activity increases regardless of extracellular signals. Signup and view all the answers

What is the consequence of introducing a mutant RTK that lacks an extracellular domain into cells with normal RTKs?

The RTK will be inactive due to inability to bind ligands. Signup and view all the answers

What mechanism is required to turn off signaling in a cell line with constitutively active Ras protein?

Blocking the interaction between protein Y and Ras. Signup and view all the answers

What occurs when insulin binds to the insulin receptor (IR)?

IRS-1 is recruited to the activated IR. Signup and view all the answers

How does the activation of a RAS-specific GEF by MEK influence signaling pathways?

It sustains RAS-GTP levels and promotes MEK activity. Signup and view all the answers

What would happen if a mutant RTK lacks its intracellular domain when expressed in a cell with normal RTKs?

The RTK will sequester ligands and inhibit normal RTKs. Signup and view all the answers

Which feedback mechanism is observed when MEK activates a RAS-specific GAP?

It provides negative feedback by reducing RAS-GTP levels. Signup and view all the answers

What effect does the growth factor SuperX have on RTK and cell proliferation?

It promotes unchecked proliferation by enhancing RTK signaling. Signup and view all the answers

What role does Ras-GEF play in the activation of Ras within receptor tyrosine kinase signaling?

It facilitates the exchange of GDP for GTP on Ras. Signup and view all the answers

What happens when the regulatory subunits of cyclic-AMP-dependent protein kinase (PKA) cannot bind the catalytic subunits?

PKA is permanently active. Signup and view all the answers

Which type of membranes are ryanodine and IP3 receptors found on?

Endoplasmic reticulum membranes. Signup and view all the answers

How does the binding of interleukin-2 to its receptor affect T lymphocytes?

It causes an increase in phosphotyrosine levels on specific proteins. Signup and view all the answers

What is a consequence of the phosphorylated tyrosine residues within the cytoplasmic domain of RTKs?

They allow interaction with various downstream adaptor proteins. Signup and view all the answers

Which of the following signals through phosphoinositide-derived messengers?

DAG and IP3. Signup and view all the answers

What is the primary mechanism by which L-Arginine aids in promoting vasodilation?

It serves as a precursor for nitric oxide production. Signup and view all the answers

Why does Ras function effectively in signaling pathways?

Ras can switch between inactive GDP-bound and active GTP-bound forms. Signup and view all the answers

What is the expected outcome when a cell-surface receptor has its extracellular domain bound by an antibody?

The receptor will be activated Signup and view all the answers

What effect do mutations in RAS genes that prevent RAS-GTP hydrolysis have on signaling pathways downstream of RAS?

Downstream pathways will be continuously active Signup and view all the answers

Which type of receptor is characterized by its ability to add phosphates to tyrosine side chains in its cytoplasmic domain upon ligand binding?

Receptor tyrosine kinase (RTK) Signup and view all the answers

Lithium, used in treating manic-depressive illness, primarily inhibits which enzymatic activity related to inositol phospholipids?

Phospholipase C activity Signup and view all the answers

Upon insulin binding to an adipocyte's insulin receptor, what primary signaling event occurs?

Tyrosine phosphorylation of the IRS docking protein Signup and view all the answers

Which signaling pathway component is specifically associated with the termination of GPCR signaling?

Phosphorylation of the receptor Signup and view all the answers

A kinase that phosphorylates inositol phospholipids and is activated by a cell surface receptor is referred to as:

Phosphoinositide 3-kinase (PI3-kinase) Signup and view all the answers

What defines a catalytic receptor in cellular signaling?

Receptor with intrinsic enzymatic activity Signup and view all the answers

What is the effect of Ras-specific GAP activity on Ras signaling in the presence of extracellular signals?

It will decrease GTP-bound Ras levels. Signup and view all the answers

How does the lack of an extracellular domain in a mutant RTK affect its functionality?

It renders the RTK inactive due to inability to bind ligands. Signup and view all the answers

What is a likely consequence of a constitutively active Ras protein?

It triggers ongoing signaling without external stimuli. Signup and view all the answers

What type of feedback is provided when MEK activates a Ras-specific GEF?

Increased Ras-GTP levels leading to positive feedback. Signup and view all the answers

What occurs to a cell line when it expresses a mutant RTK with a lack of the intracellular domain?

It might act as a dominant-negative by sequestering ligands. Signup and view all the answers

What type of signaling result is achieved when insulin binds to its receptor?

Recruitment of glucose transporters into membranes. Signup and view all the answers

How would the activation of a RAS-specific GAP by MEK impact downstream signaling?

It leads to decreased Ras-GTP and reduced MEK activity. Signup and view all the answers

What is a potential effect of the growth factor SuperX binding an RTK?

It leads to uncontrolled cell proliferation. Signup and view all the answers

Which type of receptor regulates the production of phosphoinositides through phospholipase C?

G protein-coupled receptors Signup and view all the answers

What will happen if Ras-GEF is knocked out in a cellular environment?

Ras will remain inactive Signup and view all the answers

Which protein dephosphorylates phosphoinositides, thereby reversing their signaling effects?

Phosphatase and tensin homolog (PTEN) Signup and view all the answers

How does the calcium concentration at the endoplasmic reticulum change following T lymphocyte activation?

It increases due to calcium release Signup and view all the answers

What is one role of the phosphotyrosine residues formed on proteins after receptor activation?

To recruit specific signaling proteins through SH2 domains Signup and view all the answers

Which property differentiates cyclic-AMP-dependent protein kinase (PKA) from other protein kinases?

PKA's activity is regulated by cyclic AMP Signup and view all the answers

What effect does L-Arginine have on vascular smooth muscle cells?

It promotes nitric oxide production, leading to relaxation Signup and view all the answers

What is a potential consequence of mutations in the regulatory subunit of PKA that prevent binding to catalytic subunits?

PKA will be constitutively active Signup and view all the answers

Study Notes

Ras Activation

Ras is a monomeric G protein that is activated by Ras-GEF (Guanine Nucleotide Exchange Factor) in receptor tyrosine kinase (RTK) signaling.
Ras-GEF promotes the exchange of GDP for GTP in Ras, leading to its activation.

Focal Adhesion Kinase (FAK)

FAK is a cytoplasmic tyrosine kinase found at cell-extracellular matrix (ECM) junctions.
It associates with the cytoplasmic tails of integrins.

Cyclic-AMP-Dependent Protein Kinase (PKA)

PKA is regulated by its regulatory subunits, which bind to the catalytic subunits.
Permanent activation occurs when the regulatory subunits cannot bind to the catalytic subunits, leading to constitutive activity.
Permanent inactivation occurs when the regulatory subunits bind to the catalytic subunits and cannot bind or respond to cyclic AMP, preventing activation.

Receptor Locations

Ryanodine and IP3 receptors are located on the endoplasmic reticulum (ER) membrane.
EGFR (Epidermal Growth Factor Receptor) and TGFβR (Transforming Growth Factor Beta Receptor) are localized on the plasma membrane.

Interleukin-2 Signaling

When interleukin-2 binds to its catalytic receptor on a T lymphocyte, it triggers phosphorylation of specific proteins, increasing the level of phosphotyrosines.

Phosphoinositide-Derived Messengers

Diacylglycerol (DAG) and inositol triphosphate (IP3) are examples of phosphoinositide-derived messengers.

Diversity of RTK Signaling

Activated RTKs phosphorylate tyrosine residues on different substrates, interacting with various adaptor proteins.
This interaction initiates distinct signaling pathways, allowing RTKs to activate diverse downstream cascades.

L-Arginine and Vasodilation

L-Arginine serves as a substrate for nitric oxide (NO) production.
NO promotes vasodilation by relaxing smooth muscle cells in arteries, increasing blood flow and reducing blood pressure.

Ras-Specific GAP Activity

Absence of Ras-specific GAP activity leads to sustained Ras signaling, both in the presence and absence of extracellular signals, due to increased GTP-bound Ras.

Mutant Tyrosine Kinase Receptor (RTK)

Absence of extracellular domain: The RTK becomes inactive as it cannot bind ligands.
Absence of intracellular domain: The RTK becomes inactive and might act as a dominant-negative, preventing functional receptors from binding ligands.

Constitutively Active Ras

To turn off signaling in cells with a constitutively active Ras protein, a drug that blocks protein Y from interacting with its target is needed.

Insulin Signaling

Insulin binding to the insulin receptor (IR) leads to the recruitment of the docking protein IRS-1 to the activated IR.

Feedback Mechanisms in MEK Activation

Positive feedback: Activation of a RAS-specific GEF by MEK increases RAS-GTP levels and MEK activity downstream.
Negative feedback: Activation of a RAS-specific GAP reduces RAS-GTP levels and thus MEK activity downstream.

SuperX and Cell Proliferation

A mutation that prevents the endocytosis of the RTK, preventing its degradation, would promote proliferation of cultured chicken cells in response to SuperX binding.

Mutant RAS and Signaling Pathways

Mutations in RAS genes at specific codons abolish RAS-GTP hydrolysis, leading to constitutively activated downstream pathways.

Antibody Binding to RTK

An antibody that specifically binds the extracellular domain of an RTK is expected to activate the RTK.

Lithium and Phospholipase C

Lithium, used to treat manic-depressive illness, inhibits phospholipase C activity, reducing the overproduction of IP3 and DAG associated with the illness.

Catalytic Receptors

Catalytic receptors possess either intrinsic enzymatic activity or associate with an intracellular enzyme. Examples include receptor tyrosine kinases, tyrosine-kinase-associated receptors, and protein kinase A.

Insulin Signaling in Adipocytes

Insulin binding to an insulin receptor on an adipocyte triggers Tyr phosphorylation of the docking protein IRS.

Receptor Tyrosine Kinases (RTKs)

RTKs are cell-surface receptors activated by ligand binding. They phosphorylate tyrosine side chains in their own cytoplasmic domain using ATP.

GPCR Signal Termination

Binding to arrestins is a unique process involved in GPCR signal termination.

Phosphoinositide 3-Kinase (PI3-kinase)

PI3-kinase is activated by cell-surface receptors and phosphorylates inositol phospholipids.

UZO1 Scaffolding Protein

UZO1 is a scaffolding protein that binds to pTyr, PI(3,4,5)P3 (PIP3), and proline-rich domains.
Its domains recognize these structures through specific interactions.

Ras Activation in Receptor Tyrosine Kinase Signaling

Ras is a monomeric G protein activated by Ras-GEF (Guanine nucleotide Exchange Factor).
Ras-GAP (GTPase Activating Protein) deactivates Ras.

Focal Adhesion Kinase (FAK)

FAK is a cytoplasmic tyrosine kinase located at cell-extracellular matrix (ECM) junctions.
FAK associates with the cytoplasmic tails of integrins.

Cyclic-AMP-Dependent Protein Kinase (PKA)

PKA is composed of regulatory and catalytic subunits.
PKA is permanently active if the regulatory subunits cannot bind to the catalytic subunits.
PKA is permanently inactive if the regulatory subunits bind to the catalytic subunits and cannot bind or respond to cyclic AMP.

Receptor Localization

Ryanodine and IP3 receptors are found on endoplasmic reticulum membranes.
Receptors EGFR (Epidermal Growth Factor Receptor) and TGFβR (Transforming Growth Factor Beta Receptor) are localized on plasma membranes.

Interleukin-2 Signaling

Interleukin-2 binds to its catalytic receptor on a T lymphocyte.
This binding increases the level of phosphotyrosines on specific proteins.

Phosphoinositide-Derived Messengers

Examples of phosphoinositide-derived messengers include diacylglycerol (DAG) and inositol trisphosphate (IP3).

RTK Activation of Diverse Downstream Pathways

Activated RTKs directly phosphorylate tyrosine residues on many different substrates.
Phosphorylated tyrosines in the cytoplasmic domain of RTKs interact with different adaptor proteins to initiate different signaling pathways.

L-Arginine and Vasodilation

L-Arginine promotes vasodilation by serving as a substrate for nitric oxide (NO) production.
NO relaxes smooth muscle cells in arteries, increasing blood flow and reducing blood pressure.

Ras Activity in Cells Lacking Ras-Specific GAP

Without Ras-specific GAP activity, there would be sustained Ras activity, leading to prolonged signaling in both the absence and presence of extracellular signals.

Mutations in RTK and Signaling Consequences

A mutant RTK lacking an extracellular domain is inactive because it cannot bind ligands.
A mutant RTK lacking an intracellular domain is also inactive and can act as a dominant-negative by sequestering ligands from binding to functional receptors.

Constitutively Active Ras Signaling

To turn off signaling in cells with a constitutively active Ras protein, a drug that blocks the interaction of protein Y with its target is needed.

Insulin Signaling

Insulin binding to the insulin receptor (IR) initiates downstream events that include the binding of the docking protein IRS-1 to the activated IR.

Feedback in MEK Activation

Activation of a RAS-specific GEF by MEK provides positive feedback, increasing RAS-GTP and MEK activity downstream.
Activation of a RAS-specific GAP provides negative feedback, reducing RAS-GTP and thus MEK activity downstream.

SuperX-Induced Proliferation

Mutations that prevent endocytosis of the RTK responsible for SuperX binding would promote proliferation.

RAS Mutations and Signaling Pathways

Mutations in RAS genes at specific codons that abolish RAS-GTP hydrolysis lead to constitutive activation of downstream signaling pathways.

Antibody Binding to RTK

Antibodies that specifically bind the extracellular domain of an RTK would activate the RTK.

Lithium and Inositol Phospholipid Signaling

Lithium, used in treating manic-depressive illness, may inhibit phospholipase C activity.

Catalytic Receptors

A cell-surface receptor with either intrinsic enzymatic activity or association with an intracellular enzyme is a catalytic receptor.

Insulin Receptor Signaling

When insulin binds to an insulin receptor on an adipocyte, Tyr phosphorylation of the docking protein IRS occurs.

Receptor Tyrosine Kinase (RTK)

RTKs are cell-surface receptors activated by ligand binding.
They add phosphates from ATP to tyrosine side chains in their own cytoplasmic domain.

GPCR Signal Termination - Unique Pathway

Binding to arrestins is a unique pathway in GPCR signal termination.

Phosphoinositide 3-Kinase (PI3-kinase)

PI3-kinase is a kinase that phosphorylates inositol phospholipids and is activated by a cell surface receptor.

UZO1 Scaffolding Protein

UZO1 is a scaffolding protein that binds to pTyr, PI(3,4,5)P3 (PIP3), and proline-rich domains.
The protein domains recognizing these structures include:
- SH2 domain for pTyr
- PH domain for PI(3,4,5)P3 (PIP3)
- PXXP motif (proline-rich) for proline-rich domains

Ras Activation

Ras is activated by a Ras-GEF
Ras-GEFs activate Ras by stimulating the exchange of GDP for GTP

Focal Adhesion Kinase (FAK)

FAK is a cytoplasmic tyrosine kinase
FAK is found at cell-extracellular matrix (ECM) junctions in association with the cytoplasmic tails of integrins

Cyclic-AMP-Dependent Protein Kinase (PKA)

PKA is permanently active if the regulatory subunits cannot bind the catalytic subunits
PKA is permanently inactive if the regulatory subunits bind to the catalytic subunits and cannot bind or respond to cyclic AMP

Ryanodine and IP3 Receptors

Ryanodine and IP3 receptors are located on endoplasmic reticulum membranes
EGFR and TGFβR are localized on plasma membranes

Interleukin-2

When interleukin-2 binds to its catalytic receptor on a T lymphocyte, the level of phosphotyrosines on specific proteins will increase.

Phosphoinositide-Derived Messengers

DAG and IP3 are examples of phosphoinositide-derived messengers

Receptor Tyrosine Kinases (RTKs)

Activated RTKs phosphorylate tyrosine residues on many different substrates
The phosphorylated tyrosine(s) in the cytoplasmic domain of RTKs can interact with different adaptor proteins, initiating different signaling pathways

L-Arginine

L-Arginine is a substrate for nitric oxide (NO) production
NO promotes vasodilation by relaxing smooth muscle cells in arteries, increasing blood flow and reducing blood pressure

Ras-Specific GAP Activity

Without Ras-specific GAP activity, there would be an increase in GTP-bound Ras, leading to sustained signaling

Mutant Tyrosine Kinase Receptor (RTK)

If a mutant RTK lacks an extracellular domain, the RTK will be inactive since it cannot bind ligands
If a mutant RTK lacks an intracellular domain, it may act as a dominant-negative by sequestering ligands from binding to functional receptors

Constitutively Active Ras Protein

A cell line with a constitutively active Ras protein requires a drug that blocks protein Y from interacting with its target to turn off signaling

Insulin Receptor (IR)

When insulin binds to the IR, the docking protein IRS-1 binds to the activated IR

Feedback Regulation

Activation of a RAS-specific GEF by MEK provides positive feedback, increasing RAS-GTP levels and MEK activity downstream
Activation of a RAS-specific GAP provides negative feedback, reducing RAS-GTP and thus MEK activity downstream

SuperX

A mutation that prevents endocytosis of the RTK promotes proliferation of cultured chicken cells

RAS Genes

Mutations in RAS genes at specific codons abolish RAS-GTP hydrolysis, leading to constitutively activated downstream pathways

Antibody Binding

An antibody that specifically binds the extracellular domain of an RTK would activate the RTK

Lithium

Lithium inhibits phospholipase C activity

Catalytic Receptor

A cell-surface receptor with either intrinsic enzymatic activity or association with an intracellular enzyme is a catalytic receptor

Insulin and Adipocytes

When insulin binds to an insulin receptor on an adipocyte, Tyr phosphorylation of the docking protein IRS occurs

Receptor Tyrosine Kinase (RTK)

RTKs are cell-surface receptors that are activated by ligand binding and add phosphates from ATP to tyrosine side chains in their own cytoplasmic domain

GPCR Signal Termination

Binding to arrestins is unique to GPCR signal termination

Phosphoinositide 3-Kinase (PI3-kinase)

PI3-kinases are kinases that phosphorylate inositol phospholipids and are activated by a cell surface receptor

UZO1

UZO1 is a scaffolding protein that binds to pTyr, PI(3,4,5)P3 (PIP3), and proline-rich domains.
The pTyr domain recognizes phosphorylated tyrosine residues
The PI(3,4,5)P3 (PIP3) domain recognizes phosphatidylinositol trisphosphate
The proline-rich domain recognizes proline-rich sequences in proteins

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Description

Test your knowledge on the crucial components of cell signaling, including Ras activation, Focal Adhesion Kinase (FAK), and Cyclic-AMP-Dependent Protein Kinase (PKA). This quiz also covers the locations of significant receptors like ryanodine and IP3. Dive into the intricate world of cellular communication and signaling pathways!