Erythropoietin (EPO) produced by peritubular fibroblasts of the renal cortex stimulates erythropoiesis by which receptor signalling mechanism?

• A EPO binds a GPCR on erythroid progenitors → cAMP → PKA → transcription factor phosphorylation
• B EPO binds an intrinsic tyrosine kinase receptor (like PDGFR) → autophosphorylation → PI3K → Akt
• C EPO binds the homodimeric EPO receptor → JAK2 transphosphorylation → STAT5 activation → target gene transcription (BCL-XL, cyclin D1) ✓
• D EPO binds a nuclear receptor → direct DNA binding → activation of erythroid-specific promoters

Explanation

The EPO receptor is a cytokine receptor with no intrinsic kinase activity. EPO binding causes homodimerisation and transphosphorylation of associated JAK2 tyrosine kinases. Activated JAK2 phosphorylates the receptor's cytoplasmic tail, recruiting STAT5 (and PI3K and MAPK pathways). STAT5 dimerises, translocates to the nucleus, and induces anti-apoptotic genes (BCL-XL, BCL-2) in erythroid progenitors, promoting survival and differentiation. Polycythaemia vera is caused by the gain-of-function JAK2-V617F mutation, producing EPO-independent erythropoiesis. Ruxolitinib is a JAK1/2 inhibitor used in myeloproliferative neoplasms.

Reference: Guyton & Hall, Textbook of Medical Physiology, 14th ed.

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