47. Binding of erythropoietin to its EPO receptor leads to activation of which signaling pathway?
(1) JAK-STAT pathway (2) NF-kß pathway
(3) Apaf-Smad pathway
(4) Tyrosine kinase pathway

Overview of Epo and EpoR

Erythropoietin (Epo) is a glycoprotein hormone that controls red blood cell production by binding to its receptor (EpoR) on erythroid progenitor cells. EpoR is a member of the cytokine receptor family and exists as preformed dimers on the cell surface. Activation of EpoR initiates intracellular signaling cascades critical for proliferation and survival.

Key Signaling Mechanism: JAK-STAT Pathway

• JAK2 Association: Unlike receptor tyrosine kinases, EpoR lacks intrinsic kinase activity. Instead, it is constitutively associated with the Janus kinase 2 (Jak2), a cytoplasmic tyrosine kinase.

• Ligand-Induced Activation: Binding of Epo induces conformational changes in EpoR dimers, activating Jak2.

• Autophosphorylation: Activated Jak2 autophosphorylates and phosphorylates tyrosine residues on EpoR’s cytoplasmic tail.

• STAT5 Recruitment and Activation: Phosphorylated tyrosines serve as docking sites for Signal Transducer and Activator of Transcription 5 (STAT5) proteins. Jak2 phosphorylates STAT5, which then dimerizes and translocates to the nucleus to drive transcription of erythropoiesis-related genes.

Additional Signaling Cascades

• Activation of PI3K/Akt and MAPK pathways also occurs post EpoR activation, contributing to cell survival, proliferation, and anti-apoptotic effects.

Supported by Evidence

Multiple studies (see , , ) conclusively demonstrate that EpoR signaling principally proceeds via Jak2-mediated phosphorylation and STAT5 activation, establishing the JAK-STAT cascade as the dominant pathway.​

Summary

Correct answer: (1) JAK-STAT pathway

This pathway is essential for erythroid progenitor cell proliferation and differentiation in response to Epo.