48. Receptor tyrosine kinases (RTKS) form a large and important class of cell surface receptors whose ligands are soluble or membrane bound protein or peptide hormones. Which of the following statement is INCORRECT?
(1) All RTKs are transmembrane proteins with extracellular ligand-binding site and a cytosolic domain.
(2) Binding of ligand causes most RTKs to dimerize
(3) Cytosolic tyrosine kinase phosphorylates a distinct set of tyrosine residues in the cytosolic domain of the dimer.
(4) Adapter proteins and enzymes involved in different bind to pathways signaling phosphotyrosine residues via a conserved polypeptide domain called SH2 domain.

 

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Introduction

Receptor tyrosine kinases (RTKs) are a vital class of transmembrane proteins that mediate cellular responses to diverse extracellular signals, especially protein or peptide hormones and growth factors. They are characterized by their ability to phosphorylate tyrosine residues, a key post-translational modification that triggers signaling cascades influencing cell growth, differentiation, metabolism, and more.

Core Features of RTKs

1. Structural Components: All RTKs share a common architecture comprising an extracellular ligand-binding domain, a single transmembrane helix, and an intracellular domain containing intrinsic tyrosine kinase activity.

2. Ligand-Induced Dimerization: Binding of a ligand to the extracellular domain typically induces receptor dimerization or conformational changes promoting dimerization. This dimerization is a prerequisite for activation.

3. Autophosphorylation Mechanism: Dimerization brings the kinase domains into proximity, allowing mutual (trans) autophosphorylation of specific tyrosine residues mainly in the cytoplasmic domain. These phosphorylated tyrosines serve both to increase kinase activity and create docking sites for intracellular signaling proteins.

4. Role of SH2 Domain-Containing Proteins: Adapter proteins and enzymes involved in downstream signaling recognize and bind to phosphorylated tyrosines via conserved Src homology 2 (SH2) domains, enabling assembly of signaling complexes and propagation of the signal to various pathways like RAS/MAPK and PI3K/Akt.

Evaluating the Statements

• (1) All RTKs are transmembrane proteins with extracellular ligand-binding sites and a cytosolic domain. This is correct.

• (2) Binding of ligand causes most RTKs to dimerize. This is correct.

• (3) Cytosolic tyrosine kinase phosphorylates a distinct set of tyrosine residues in the cytosolic domain of the dimer. This is correct.

• (4) Adapter proteins and enzymes involved in different signaling pathways bind to phosphotyrosine residues via a conserved polypeptide domain called SH2 domain. This is correct in principle, but the statement is grammatically awkward and potentially misleading as written — it implies these proteins bind “in different to pathways signaling phosphotyrosine residues,” which is unclear.

However, all four statements accurately describe RTKs and their signaling, but if we carefully consider some subtle wording, statement (4) seems the least precise or has an awkward phrase.

Potential Clarification

Statement (4) is intended to communicate that adapter and signaling proteins recognize phosphotyrosines created by RTK autophosphorylation through SH2 domains, a broadly established fact.

Since all four statements reflect accepted knowledge, the incorrectness might hinge on the clarity or syntax rather than content.

Summary

• RTKs have an extracellular ligand-binding domain, a transmembrane domain, and cytosolic tyrosine kinase domain.

• Ligand binding typically induces RTK dimerization, activating kinase functions.

• Kinase domains autophosphorylate tyrosine residues on the partner receptor.

• SH2-domain-containing proteins bind these phosphotyrosines, linking to downstream signaling cascades.

No major factual errors are present in the options; the slight ambiguity is only in statement (4) phrasing.

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