Erythropoietin (EPO) receptor signaling uses the JAK-STAT pathway. Which specific Janus kinase and STAT mediates EPO's antiapoptotic and proliferative effects in erythroid progenitors?
- A JAK1 phosphorylates STAT3; STAT3 dimers activate erythroid transcription exclusively
- B JAK2 phosphorylates STAT5; activated STAT5 homodimers translocate to the nucleus and induce Bcl-xL (antiapoptotic), cyclin D, and other erythroid differentiation genes ✓
- C JAK2 phosphorylates STAT1; STAT1 activates interferon response genes that crossactivate erythropoiesis
- D TYK2 phosphorylates STAT6; STAT6 induces hemoglobin synthesis genes
Explanation
The EPO receptor is a homodimeric cytokine receptor that, upon EPO binding, activates preassociated JAK2. Activated JAK2 transphosphorylates both JAK2 and the EPO receptor cytoplasmic domain, creating docking sites for STAT5. STAT5 is phosphorylated (Tyr694), dimerizes, translocates to the nucleus, and activates gene transcription including Bcl-xL (preventing apoptosis of erythroid progenitors), c-myc, and cyclin D. This explains why JAK2 V617F gain-of-function mutation causes EPO-independent erythrocytosis in polycythemia vera — constitutive STAT5 activation drives unchecked red cell production.
Reference: Guyton & Hall, Textbook of Medical Physiology, 14th ed.
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