Role of p38 MAPK and MAPKAPK-2 in angiotensin II-induced Akt activation in vascular smooth muscle cells.

Angiotensin II activates a variety of signaling pathways in vascular smooth muscle cells (VSMCs), including the MAPKs and Akt, both of which are required for hypertrophy. However, little is known about the relationship between these kinases or about the upstream activators of Akt. In this study, we tested the hypothesis that the reactive oxygen species kinase p38 MAPK and its substrate mediate Akt activation in VSMCs. In unstimulated VSMCs, Akt and p38 MAPK are constitutively associated and remain so after angiotensin II stimulation. Inhibition of p38 MAPK activity with SB-203580 dose-dependently inhibits Akt phosphorylation on Ser(473), but not Thr(308). Angiotensin II-induced phosphorylation of MAduanyu1529PK-2 is also attenuated by SB-203580, as well as by inhibitors of In addition, angiotensin II stimulates the association of MAduanyu1529PK-2 with the Akt-p38 MAPK complex, and an in vitro kinase assay shows that MAduanyu1529PK-2 immunoprecipitates of VSMC lysates phosphorylate recombinant Akt in an angiotensin II-inducible manner. Finally, intracellular delivery of a MAduanyu1529PK-2 peptide inhibitor blocks Akt phosphorylation on Ser(473). These results suggest that the p38 pathway mediates Akt activation by angiotensin II in these cells by recruiting active MAduanyu1529PK-2 to a signaling complex that includes both Akt and p38 MAPK. Through this mechanism, p38 MAPK confers sensitivity to Akt and facilitates downstream signaling. These results provide evidence for a novel signaling complex that may help to spatially organize hypertrophy-related, signaling in VSMCs.

KEYWORDS: {{ getKeywords(articleDetailText.words) }}