Abstract
We demonstrate here that growth hormone (GH) stimulates the activation of RhoA and its substrate Rho kinase (ROCK) in NIH-3T3 cells. GH-stimulated formation of GTP-bound RhoA requires JAK2-dependent dissociation of RhoA from its negative regulator p190 RhoGAP. Inactivation of RhoA does not affect GH-stimulated JAK2 tyrosine phosphorylation nor p44/42 MAPK activity. However, RhoA and ROCK activities are required for GH-stimulated, Stat5-mediated transcription. RhoA-dependent enhancement of GH-stimulated, Stat5-mediated transcription is due to repression of histone deacetylase 6 activity recruited by transcription cofactor p300 that negatively regulates GH-stimulated, Stat5-mediated transcription. We also demonstrate that RhoA is the pivot for cAMP-dependent protein kinase inhibition of GH-stimulated, Stat5-mediated transcription as a consequence of cAMP-dependent protein kinase inactivation of RhoA through serine residue 188 of RhoA. We have therefore provided a novel mechanism by which a Ras-like small GTPase, RhoA, can regulate Stat5-mediated transcription.
Highlights
RhoA belongs to the Rho subfamily of the Ras-related, small GTPase superfamily that consists of five groups as follow: Ras, Rho, Rab, Arf, and Ran [1]
As we have demonstrated that growth hormone (GH)-stimulated formation of RhoA-GTP requires JAK2 kinase activity and subsequent inactivation of p190 RhoGAP, we further examined the dependence of GH-stimulated ROCK activity on JAK2 and p190 RhoGAP
Forced expression of the p300⌬CRD1 mutant prevented inhibition of GH-stimulated, Stat5-mediated transcription as a consequence of forced expression of HDAC6 (Fig. 8C), indicating that HDAC6 association with p300 is required for repression of GH-stimulated, Stat5-mediated transcription
Summary
RhoA belongs to the Rho subfamily of the Ras-related, small GTPase superfamily that consists of five groups as follow: Ras, Rho, Rab, Arf, and Ran [1]. RhoA and ROCK activities are required for GH-stimulated, Stat5-mediated transcription. We identify PKA as a negative regulator of GH-stimulated, Stat5-mediated transcription, and this cellular effect of PKA requires the PKA phosphorylatable serine residue 188 of RhoA.
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