Receptor Tyrosine Kinases (RTKs) Overview
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Questions and Answers

What is the role of phosphorylated tyrosine residues in Receptor Tyrosine Kinases (RTKs)?

  • They catalyze the degradation of the receptor.
  • They act as docking sites for adapter proteins. (correct)
  • They serve as binding sites for signaling molecules.
  • They inhibit kinase activity.

Which protein is mentioned as an example that binds through the SH2 domain to activated RTKs?

  • Grb2 (correct)
  • PI3 kinase
  • IRS1
  • Src

What initiates the activation of intracellular signaling in Receptor Tyrosine Kinases?

  • Cross phosphorylation of tyrosine residues (correct)
  • Binding of ligands to the receptor
  • Dissociation of adapter proteins
  • Phosphorylation of target proteins

How does the insulin receptor contribute to cellular signaling?

<p>By autophosphorylating and catalyzing phosphorylation of target proteins (C)</p> Signup and view all the answers

Which of the following proteins is specifically activated by binding to an activated PDGF receptor?

<p>PI3 kinase (A)</p> Signup and view all the answers

What happens to Ras when GTP is bound to it?

<p>It becomes active. (A)</p> Signup and view all the answers

Which kinase is directly activated by Ras?

<p>raf-1 MAP kinase kinase kinase (C)</p> Signup and view all the answers

What is the primary role of MEK in the kinase cascade?

<p>To phosphorylate MAPK. (A)</p> Signup and view all the answers

What effect does the phosphorylation of transcription factors like fos and jun have?

<p>They bind to DNA and alter gene transcription. (A)</p> Signup and view all the answers

What is the significance of the kinase cascade initiated by Ras?

<p>It creates a signal amplification mechanism. (B)</p> Signup and view all the answers

What role does AKT play in cellular metabolism?

<p>Increases the activity of Glut4 (B)</p> Signup and view all the answers

Which component directly activates Ras in the signaling pathway?

<p>GEF (C)</p> Signup and view all the answers

What is the primary function of the GAP protein in the Ras signaling pathway?

<p>Increases intrinsic GTPase activity (C)</p> Signup and view all the answers

Which of the following statements about receptor tyrosine kinases (RTKs) is correct?

<p>RTKs act as signal transducers for multiple pathways. (B)</p> Signup and view all the answers

What is a major consequence of persistent activation of Ras due to dominant mutations?

<p>Enhanced cellular division and potential cancer formation (C)</p> Signup and view all the answers

Which statement accurately describes the PI3 kinase signaling pathway?

<p>It is involved in the activation of AKT. (C)</p> Signup and view all the answers

What is the outcome of MAP kinases phosphorylating transcription factors?

<p>Regulation of cell cycle and differentiation (B)</p> Signup and view all the answers

How are protein kinase cascades advantageous in signal transduction?

<p>Amplifies the signal at multiple stages. (B)</p> Signup and view all the answers

What is the initial event that occurs upon ligand binding to a Receptor Tyrosine Kinase (RTK)?

<p>Autophosphorylation of the receptor (C)</p> Signup and view all the answers

What is true about the structure of most Receptor Tyrosine Kinases?

<p>They have an extracellular ligand binding domain and a cytosolic kinase domain. (B)</p> Signup and view all the answers

Which of the following ligands can cross bind to Receptor Tyrosine Kinases?

<p>Insulin and Insulin-like Growth Factor 1 (IGF1) (C)</p> Signup and view all the answers

What is the role of heterodimerization in the activation of Receptor Tyrosine Kinases?

<p>It initiates changes that lead to kinase activation. (A)</p> Signup and view all the answers

Which statement is true concerning ligand shedding in RTK signaling?

<p>It is mediated by proteases that cleave the ligand. (C)</p> Signup and view all the answers

What consequence does receptor dimerization have on RTKs?

<p>It triggers cross-phosphorylation of the receptors. (B)</p> Signup and view all the answers

What defines the unique function of Receptor Tyrosine Kinases compared to other receptor types?

<p>They have intrinsic kinase activity that facilitates phosphorylation. (B)</p> Signup and view all the answers

What is commonly found in the structure of Receptor Tyrosine Kinases?

<p>An N-terminal extracellular ligand binding domain. (D)</p> Signup and view all the answers

Which biological processes are commonly associated with Receptor Tyrosine Kinases?

<p>Regulation of growth and differentiation. (D)</p> Signup and view all the answers

What type of signaling process is initiated following ligand-receptor interaction in RTKs?

<p>Propagation of intracellular signaling cascades (D)</p> Signup and view all the answers

What initiates the activation of Ras in the signaling pathway?

<p>Exchange of GDP for GTP by Sos (D)</p> Signup and view all the answers

Which domain of the GRB2 protein allows it to bind to receptor phosphotyrosine residues?

<p>SH2 domain (C)</p> Signup and view all the answers

What role does the protein Sos play in the activation of Ras?

<p>It acts as a GEF to promote GDP-GTP exchange (D)</p> Signup and view all the answers

How does the activated Ras-GTP complex affect downstream signaling?

<p>It activates the MAP kinase pathway (B)</p> Signup and view all the answers

What happens to the Ras protein after it is activated by Sos?

<p>It dissociates from Sos but remains membrane-tethered (C)</p> Signup and view all the answers

Which of the following correctly describes the process of receptor activation by EGF?

<p>Receptor dimerization leads to autophosphorylation on tyrosine residues (C)</p> Signup and view all the answers

What is a primary function of Ras in signaling pathways?

<p>To amplify signals sent from the receptor (B)</p> Signup and view all the answers

How does the activation of receptor tyrosine kinases influence the SH2 domain protein interactions?

<p>It creates a binding site for proteins with SH2 domains (D)</p> Signup and view all the answers

Flashcards

RTK Activation

Receptor Tyrosine Kinases (RTKs) are activated when a ligand binds to the receptor, causing a conformational change. This change leads to the receptor's autophosphorylation, initiating a signaling cascade.

Cross-Phosphorylation

When two RTKs bind to a ligand, they bring their kinase domains close together. These domains then phosphorylate each other on specific tyrosine residues, fully activating their kinase activity.

Docking Sites & Adapter Proteins

Phosphorylated tyrosine residues on activated RTKs act as docking sites for adapter proteins, which can bind via their SH2 domains. These adapter proteins then recruit other signaling molecules, triggering downstream signaling events.

PI3 Kinase

PI3 Kinase is a signaling molecule that binds to activated RTKs through its SH2 domain. Once bound, it gets activated and initiates downstream signaling pathways, often related to cell growth and metabolism.

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Regulation of RTKs

RTKs can be regulated through various mechanisms, including the binding of antibodies to specific tyrosine phosphorylation sites. This can distinguish between different types of receptors, and modulate their activity.

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RTKs

Receptor Tyrosine Kinases are cell surface receptors directly linked to intracellular enzymes (kinases). They are involved in signal transduction, primarily responding to growth factors like PDGF, NGF, EGF, FGF, VEGF, insulin, and IGF1.

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Ligand Binding

The process where a signaling molecule (ligand) binds to the extracellular domain of an RTK.

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Receptor Activation

Upon ligand binding, RTKs undergo conformational changes, often dimerization, leading to activation of their intracellular kinase activity.

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Autophosphorylation

Activated RTKs phosphorylate themselves on tyrosine residues, creating docking sites for other signaling molecules.

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Signal Transmission

Phosphorylated tyrosine residues on the RTK act as docking sites for signaling proteins, triggering a cascade of intracellular events.

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RTK Dimerization

Ligand binding often leads to the dimerization of two RTK molecules, bringing their kinase domains close together.

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Tyrosine Kinase Activity

The intrinsic enzyme activity of RTKs that phosphorylates tyrosine residues on proteins, including themselves.

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Docking Sites

Phosphorylated tyrosine residues on activated RTKs serve as binding sites for other signaling proteins, allowing them to assemble at the receptor.

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Signal Transduction Pathway

The series of events that occur after ligand binding, involving protein interactions, phosphorylation, and activation of downstream signaling molecules.

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Diverse Functions of RTKs

RTKs play vital roles in various cellular processes, including cell growth, differentiation, metabolism, and survival. Different RTKs are activated by distinct ligands, leading to specific downstream signaling pathways.

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Raf-1 Kinase

Raf-1 is a cellular kinase activated by Ras. It plays a crucial role in the MAP kinase pathway by phosphorylating MEK.

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Kinase Cascade

A series of protein kinases sequentially activating each other via phosphorylation, leading to amplification of the signal.

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Ras Tethering

Ras is anchored to the membrane, preventing its free movement and ensuring its localization near signaling pathways.

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SOS Role

SOS, a GEF protein, facilitates the activation of Ras by helping it exchange GDP for GTP.

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GRB2 Binding

GRB2, an adaptor protein, connects the receptor to SOS, bringing them together to initiate Ras activation.

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EGF Receptor Dimerization

When EGF binds to its receptor, the receptors come together (dimerize), triggering a cascade of events.

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Tyrosine Kinase Receptor Phosphorylation

Upon dimerization, the receptor's tyrosine kinase domain adds phosphate groups (phosphorylates) to specific tyrosine residues.

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SH2 Domain Binding

Proteins with an SH2 domain recognize and bind to phosphorylated tyrosine residues on the receptor, initiating downstream signaling.

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Ras-GTP Complex Activation

The active Ras-GTP complex detaches from SOS and activates the MAP kinase pathway, leading to cellular responses.

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MAP kinase pathway

The MAP kinase pathway is a signaling cascade that plays a vital role in regulating cell growth, proliferation, differentiation, and stress responses. It involves a series of protein kinases that sequentially phosphorylate and activate each other, ultimately affecting gene expression.

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Oncogenes

Oncogenes are genes that can cause cancer when abnormally activated or expressed. These genes often encode proteins involved in regulating cell growth, proliferation, and survival, but mutations can lead to uncontrolled cell division.

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Dominant Ras Mutations

Dominant Ras mutations are genetic alterations that render Ras constitutively active, bypassing normal regulatory mechanisms. These mutations often occur in the GTPase domain, preventing Ras from switching off, leading to uncontrolled growth signaling and cancer development.

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Study Notes

Receptor Tyrosine Kinases (RTKs)

  • RTKs are cell surface receptors directly linked to intracellular enzymes (kinases)
  • Many growth factor receptors are part of this family, including PDGF, NGF, EGF, FGF, VEGF, insulin, and IGF1
  • Receptors can be single polypeptides or dimers (two single peptides that dimerize upon ligand activation)

Learning Outcomes

  • This lecture introduces the tyrosine kinase-linked receptors (RTKs)
  • Includes ligand binding and receptor activation
  • Describes signal initiation and transmission (players)
  • Explains diverse functions of RTKs
  • Investigates implications in biological processes

Overview of RTKs: Family Members

  • Insulin and IGF1 can cross-bind
  • Includes receptors like EGF, insulin, IGF-1, NGF, FGF, PDGF, M-CSF, VEGF, Eph receptor
  • Each type has its own unique domains (e.g., cysteine-rich, tyrosine kinase, immunoglobulin-like)

Overview of RTKs: Structure

  • RTKs have an extracellular ligand-binding domain
  • A single-pass transmembrane α-helix
  • A cytosolic C-terminal domain with intrinsic tyrosine kinase activity
  • Ligand binding triggers autophosphorylation of the receptor

Mechanism of Activation: Receptor-Ligand Binding

  • Ligands form dimers through disulfide bonds
  • Ligands bind to two identical receptor binding sites
  • Binding of the hormone causes receptor dimerization
  • Initiates intracellular signaling

Mechanism of Activation: Receptor Dimerization and Kinase Activation

  • Receptor dimerization leads to autophosphorylation
  • Each receptor cross-phosphorylates a specific tyrosine residue on its counterpart
  • Activation of its kinase activity

Mechanism of Activation: Docking of signaling molecules at RTK

  • Phosphorylated tyrosine residues on RTKs become docking sites for adapter proteins
  • These adapter proteins can be proteins like Grb2, which have SH2 domains

Mechanism of Activation: The Binding of SH2-containing signaling proteins

  • Phosphorylated tyrosines can be specifically identified by SH2 domains on other proteins, including adapter proteins
  • Activated receptors can phosphorylate these bound proteins
  • This leads to intracellular signal transmission

Initiation of Cellular Response

  • 2 insulin molecules bind and induce a conformational change in the receptor
  • Autophosphorylates and catalyzes phosphorylation of target proteins like IRS1
  • Initiates multiple cellular responses (e.g., insulin signaling activates glucose transport)

Transduction of Response

  • Protein kinase cascades amplify signals at each step
  • Information received at the plasma membrane is communicated to the nucleus
  • Multiple steps in the pathway provide specificity
  • Various target proteins provide diversity in response

RTK Signaling: Ras Pathway

  • Ras is a monomeric GTPase switch protein
  • Activation is enhanced by GEF (guanine nucleotide exchange factor)
  • GDP-GTP exchange leads to activation
  • Deactivation requires GAP (GTPase-activating proteins) that increase intrinsic GTPase activity
  • Once active, Ras propagates signaling through a MAP kinase cascade
  • Mutant RTKs or Ras/MAP kinase signaling proteins are linked with nearly all cancers

Ras activation mechanism

  • EGF binding causes receptor dimerization and autophosphorylation
  • GRB2 binds to phosphorylated tyrosines; GRB2 contains SH3 domains that allow SOS protein to bind to the membrane complex
  • SOS then recruits Ras to the complex
  • SOS promotes GTP exchange for GDP on Ras
  • Active Ras-GTP complex dissociates from Sos
  • Active Ras then activates the MAP kinase portion of the signaling pathway

Mechanism of Tyrosine Kinase Receptors

  • Hormone binding causes receptor dimerization/aggregation
  • Receptor tyrosine kinase domains phosphorylate C-terminal tyrosines
  • Phosphorylation produces binding sites for proteins with SH2 domains (e.g., GRB2 with bound SOS)
  • SOS is a GEF that activates Ras by exchanging GDP for GTP
  • Activated Ras activates Raf-1 kinase, MEK, and MAPK kinase, resulting in a kinase cascade
  • Kinase cascade triggers changes in gene expression which regulate protein activity

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