In the JAK-STAT signaling pathway activated by growth hormone (GH), which sequence of events correctly describes signal transduction from receptor activation to gene transcription?

• A GH binds monomeric GHR → Gs activation → cAMP rise → PKA phosphorylates STAT5 → nuclear translocation
• B GH binds GHR dimer → JAK2 cross-phosphorylates → RAS-MAPK cascade → direct transcription factor activation
• C GH binds monomeric GHR → JAK2 auto-phosphorylates → STAT5 phosphorylated → STAT5 dimer translocates to nucleus → GH-responsive gene transcription ✓
• D GH binds GHR → IP3-mediated calcium release → calmodulin kinase → STAT5 activation

Explanation

Growth hormone binds GHR and induces receptor dimerization (not initial monomer binding). JAK2 (pre-associated with each GHR subunit) becomes activated by trans-phosphorylation. JAK2 then phosphorylates tyrosine residues on the receptor, creating docking sites for STAT5. STAT5 is tyrosine-phosphorylated, dimerises, and translocates to the nucleus to drive IGF-1 and other GH-responsive gene expression. GH does not signal via Gs/cAMP or PLC-IP3 as primary pathways.

Reference: Harper's Illustrated Biochemistry, 32nd ed.

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