PDK1 recruitment to the SHPS-1 signaling complex enhances insulin-like growth factor-i-stimulated AKT activation and vascular smooth muscle cell survival.

The Journal of Biological Chemistry
Xinchun ShenDavid R Clemmons

Abstract

In vascular smooth muscle cells, exposed to hyperglycemia and insulin-like growth factor-I (IGF-I), SHPS-1 functions as a scaffold protein, and a signaling complex is assembled that leads to AKT activation. However, the underlying mechanism by which formation of this complex activates the kinase that phosphorylates AKT (Thr(308)) is unknown. Therefore, we investigated the mechanism of PDK1 recruitment to the SHPS-1 signaling complex and the consequences of disrupting PDK1 recruitment for downstream signaling. Our results show that following IGF-I stimulation, PDK1 is recruited to SHPS-1, and its recruitment is mediated by Grb2, which associates with SHPS-1 via its interaction with Pyk2, a component of the SHPS-1-associated complex. A proline-rich sequence in PDK1 bound to an Src homology 3 domain in Grb2 in response to IGF-I. Disruption of Grb2-PDK1 by expression of either a Grb2 Src homology 3 domain or a PDK1 proline to alanine mutant inhibited PDK1 recruitment to SHPS-1, leading to impaired IGF-I-stimulated AKT Thr(308) phosphorylation. Following its recruitment to SHPS-1, PDK1 was further activated via Tyr(373/376) phosphorylation, and this was required for a maximal increase in PDK1 kinase activity and AKT-mediated FOXO3a ...Continue Reading

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Citations

Oct 19, 2011·Journal of Bone and Mineral Research : the Official Journal of the American Society for Bone and Mineral Research·Victoria E DeMambroDavid Clemmons
Apr 10, 2015·American Journal of Physiology. Cell Physiology·Yi Ran NoC Chris Yun
Aug 2, 2015·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Gang XiDavid R Clemmons
Mar 5, 2015·Journal of Cardiovascular Pharmacology and Therapeutics·Zhi-Liang YuJian-Ming Jiang

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