Biochemistry: Enzyme-Coupled Receptors

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Questions and Answers

What is the primary function of receptor tyrosine kinases (RTKs) in cellular processes?

They regulate ion channels in response to hormones.

They act primarily as neurotransmitters in the synapse.

They regulate cell differentiation and proliferation. (correct)

They facilitate the cross-linking of signaling proteins.

Which of the following statements accurately describes the behavior of ligand binding to RTKs?

Ligand binding does not lead to receptor dimerization.

All RTK ligands are exclusively membrane-bound.

Ligands exclusively bind to monomeric receptors.

Binding activates pre-existing receptor dimers in some cases. (correct)

How does receptor dimerization influence the activity of RTKs?

It prevents autophosphorylation from occurring.

It activates the kinase domains for cross-phosphorylation. (correct)

It enables the receptors to bind additional ligands.

It decreases the affinity of the receptors for intracellular signaling proteins.

Which signaling pathway is primarily activated by receptor tyrosine kinases?

Monomeric GTPase Ras signaling pathway. Signup and view all the answers

What is the role of PI 3-Kinase activated by RTKs?

It generates lipid docking sites in the plasma membrane. Signup and view all the answers

What specifically occurs at the activation lip during the phosphorylation process in RTKs?

It undergoes autophosphorylation leading to conformational changes. Signup and view all the answers

Which of the following best describes how signaling proteins can cross-link receptor chains?

Through clustering on the membrane after ligand binding. Signup and view all the answers

In what way do RTKs contribute to complex cell behaviors?

They form networks of protein kinase activities to integrate signals. Signup and view all the answers

What role do GTPase-activating proteins (GAPs) play in Ras signaling?

They stimulate GTP hydrolysis to inactivate Ras. Signup and view all the answers

Which of the following statements about MAP kinases is true?

They contribute to signal propagation after Ras activation. Signup and view all the answers

What is the effect of high ligand concentrations on cell-surface receptors?

Receptors are internalized and may be degraded. Signup and view all the answers

Which protein is NOT typically classified as a GEP for Ras?

p120 RasGAP Signup and view all the answers

What consequence is associated with mutant RTKs in Ras/MAP kinase signaling?

They contribute to deregulation of signaling pathways. Signup and view all the answers

Which cellular process is most directly controlled by RTK-Ras/MAP kinase signaling?

Cell division and differentiation Signup and view all the answers

Why is resensitization of internalized RTKs important?

It ensures that sufficient receptor molecules are present for signaling. Signup and view all the answers

What is a common result of dominant Ras mutations?

They lead to permanent activation of Ras. Signup and view all the answers

What is the primary role of MAP kinase in the signaling pathway?

To phosphorylate downstream target proteins Signup and view all the answers

Which protein is responsible for promoting the exchange of GDP for GTP on Ras?

Sos Signup and view all the answers

What kind of protein is Ras classified as, according to its structure and function?

Monomeric GTPase Signup and view all the answers

What is the consequence of MAP kinase phosphorylating gene regulatory proteins?

Alteration of gene expression and cellular behavior Signup and view all the answers

What triggers the activation of Ras in the signaling pathway?

Binding of EGF to its receptor Signup and view all the answers

Which domain of GRB2 is essential for binding to phosphotyrosine residues on the receptor?

SH2 domain Signup and view all the answers

How does Ras remain associated with the inner leaflet of the membrane after activation?

Via a lipid anchor sequence Signup and view all the answers

What is one of the activities regulated by the activation of MAP kinase?

Change in cell proliferation and differentiation Signup and view all the answers

What role does Akt primarily play in the PI-3-kinase signaling pathway?

Promotes the growth and survival of cells Signup and view all the answers

What is the function of phosphatase PTEN in the PI-3-kinase signaling pathway?

Terminates PI 3-phosphate signaling Signup and view all the answers

Which protein does Akt phosphorylate to inhibit apoptosis?

Bad Signup and view all the answers

How is PKB (Akt) activated in the signaling pathway?

By being recruited to the membrane via binding to PI 3-phosphates Signup and view all the answers

What is the result of insulin stimulation in muscle cells and adipocytes regarding Akt?

Activates glycogen synthase Signup and view all the answers

What happens when glycogen synthase kinase is phosphorylated by Akt?

It stimulates glycogen synthesis Signup and view all the answers

In the context of cancer, what is notable about PTEN?

PTEN is inactive in many advanced cancers Signup and view all the answers

What does Akt primarily influence in the PI-3-kinase signaling pathway?

Cell survival and growth Signup and view all the answers

What is the primary function of activated RTKs in relation to intracellular signaling proteins?

They recruit and activate a complex of intracellular signaling proteins. Signup and view all the answers

Which monomeric GTPase is primarily activated by RTKs?

Ras Signup and view all the answers

What role do phosphorylated lipids play in receptor signaling?

They become docking sites for specific intracellular signaling proteins. Signup and view all the answers

How do RTKs signal via the Phosphatidyl-inositol 3-kinase (PI3K) pathway?

By activating PI3-kinase to promote cell growth and survival. Signup and view all the answers

In the signaling pathway of RTKs, what distinguishes the activation of phospholipase C (PLC) compared to GPCRs?

RTKs activate PLCγ isoform instead of PLCβ. Signup and view all the answers

Which of the following is a direct consequence of activating the PI3K pathway by RTKs?

Promotion of cell growth and survival. Signup and view all the answers

What is the function of the SH2 domain in the signaling pathway activated by RTKs?

It binds to activated RTKs to facilitate further signaling. Signup and view all the answers

What type of signaling mainly involves the pathway that RTKs utilize for promoting cell survival?

Phosphatidyl-inositol 3-phosphate signaling. Signup and view all the answers

What initiates the activation of Janus kinases (JAKs) in the JAK-STAT signaling pathway?

Binding of cytokines to the receptor Signup and view all the answers

In the JAK-STAT pathway, what is the role of phosphorylated tyrosine residues?

They create docking sites for STAT proteins Signup and view all the answers

What is the final outcome of the JAK-STAT signaling pathway?

Transactivation of specific target genes Signup and view all the answers

Which of the following components are primarily responsible for the phosphorylation of the receptor in the JAK-STAT pathway?

Janus kinases (JAKs) Signup and view all the answers

Which step directly follows the phosphorylation of STAT proteins in the JAK-STAT signaling pathway?

Translocation into the nucleus Signup and view all the answers

How do activated STAT proteins form dimers in the JAK-STAT pathway?

Through phosphorylation by JAKs Signup and view all the answers

What role does receptor dimerization play in the JAK-STAT signaling pathway?

Allows JAKs to become transphosphorylated Signup and view all the answers

What is a significant example of a cytokine that activates the JAK-STAT pathway?

Prolactin Signup and view all the answers

Study Notes

Session Learning Outcomes (SLOs)

SLO# 1: Define kinases and phosphatases and their role in signal transduction.
SLO# 2: Explain the different mechanisms by which cells regulate and/or terminate responses to chemical signals.

Enzyme-Coupled Receptors

Enzyme-coupled receptors are transmembrane proteins.
These proteins display their ligand-binding domain on the outer surface of the plasma membrane.
The cytoplasmic domain of the receptor either acts as an enzyme itself or forms a complex with another protein that acts as an enzyme.

Receptor Tyrosine Kinases (RTKs)

RTKs are the largest class of enzyme-coupled receptors.
They consist of cytoplasmic domains functioning as tyrosine protein kinases.
These kinases phosphorylate specific tyrosine amino acids on selected intracellular proteins.
RTKs regulate cell differentiation and proliferation.
RTK ligands are soluble or membrane-bound peptides/proteins, including NGF, PDGF, FGF, EGF, and insulin.
Ligand binding typically causes receptor dimerization. (Some RTKs, like insulin RTK, bind to pre-existing dimers.)

Signaling Proteins

Several signaling proteins act via RTKs. Specific ligands trigger specific receptor-mediated responses.
Example signaling proteins include EGF, insulin, IGF, NGF, PDGF, M-CSF, FGF, VEGF, and Ephrins.
Their receptors, resulting downstream processes, and impact on various cell types are described in a table.
Receptor tyrosine kinases (RTKs) are involved in many biological processes and their mutations are linked to cancer.

Enzyme-Coupled Receptors Signaling

Activated RTKs recruit a complex of intracellular signaling proteins.
Most RTKs activate the monomeric GTPase Ras.
RTKs activate PI 3-kinase to produce lipid docking sites in the plasma membrane.
Some receptors activate a fast track to the nucleus.
Protein kinase networks integrate information to control complex cellular behaviors.

RTK signal pathways

Almost all RTKs signal via the Ras/MAP kinase pathway.
Some also use other pathways, such as the PI-3 kinase pathway found in the insulin receptor.
This pathway regulates gene expression and enzyme activity, such as glycogen synthase.

Ras Activation

Ras is a small protein bound by a lipid tail to the plasma membrane's cytoplasmic face.
Ras-activating protein causes Ras to exchange GDP for GTP.
Active Ras then triggers subsequent steps in the signaling pathway.
Ras activation is aided by adapter proteins, like GRB2, and associated guanine nucleotide exchange factors (GEFs) like Sos.

The MAP Kinase Pathway

The MAP kinase pathway is a crucial step in relaying signals from cell-surface receptors to the nucleus.
MAP kinase phosphorylates target proteins, including other protein kinases and gene regulatory proteins.
Changes in gene expression and protein activity result in different cellular responses, such as cell proliferation and differentiation.
In this pathway activated RAS triggers a phosphorylation cascade involving various kinases like Raf kinase, MEK, and MAP kinase to ultimately change gene activity in the cell nucleus.

Activation and Inhibition of RTKs and Signaling Cascades

RTKs use a cascade of activation steps to signal throughout the cell.
Excessive ligand concentration can lead to internalization of receptors, reducing the cell's responsiveness.
Internalized RTKs are degraded in lysosomes, with subsequent resensitization reliant on receptor synthesis.
Mutant RTKs or Ras/MAP kinase signaling proteins are linked to virtually all cancers. Certain mutations cause Ras to be stuck in an "on-state" constantly activating signaling pathways leading to unregulated cell growth.

Signaling via Phosphatidyl-inositol 3-phosphates

PI3-kinase is an enzyme that can phosphorylate inositol phospholipids in the plasma membrane.
This phosphorylation creates docking sites for intracellular signaling proteins, which relocate to the membrane and activate each other.
Akt is a key protein for promoting cell survival by inactivating the protein Bad.
Akt activates Tor leading to protein synthesis, inhibiting protein degradation and promoting cell growth.

Other Signaling Pathways

Cytokines activate JAK-STAT signaling pathway, beginning with cytokine binding to a receptor.
This leads to receptor dimerization, JAK activation, STAT binding/phosphorylation, and translocation to the nucleus, ultimately affecting gene transcription.
The different components of RTK signalling pathways are summarized.

Summary

Receptor tyrosine kinases (RTKs) bind to peptide hormones and may dimerize.
Ligand binding activates RTK kinase activity and autophosphorylation, which activates downstream signaling.
Ras, an intracellular GTPase switch, acts downstream of most RTKs.
RTKs are linked to Ras indirectly through adapter proteins such as GRB2 and Sos.
The MAP kinase pathway is a critical downstream signaling cascade from Ras involved in gene regulation and cell processes like proliferation and differentiation.
Activated Ras triggers a cascade of phosphorylation that culminates in transcription factor activation and gene expression changes.

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Description

This quiz explores the functions and mechanisms of enzyme-coupled receptors, focusing on kinases and phosphatases in signal transduction. You will learn about Receptor Tyrosine Kinases (RTKs) and their role in regulating cell differentiation and proliferation. Test your understanding of these crucial biochemical concepts.