Deletion of PDK1 Caused Cardiac Malmorphogenesis and Heart Defects Due to Profound Protein Phosphorylation Changes Mediated by SHP2.

Phosphoinositide-dependent protein kinase-1 (PDK1), a master kinase and involved in multiple signaling transduction, participates in regulating embryonic cardiac development and postnatal cardiac remodeling. Germline PDK1 knockout mice displayed no heart development; in this article, we deleted PDK1 in heart tissue with different cre to characterize the temporospatial features and find the relevance with congenital heart disease(CHD), furthermore to investigate the underlying mechanism. Knocking out PDK1 with Nkx2.5-cre, the heart showed prominent pulmonic stenosis. Ablated PDK1 with Mef2cSHF-cre, the second heart field (SHF) exhibited severe hypoplasia. And deleted PDK1 with αMHC-cre, the mice displayed dilated heart disease, protein analysis indicated PI3K and ERK were activated; meanwhile, PDK1-AKT-GSK3, and S6K-S6 were disrupted; phosphorylation level of Akt473, S6k421/424, and Gsk3α21 enhanced; however, Akt308, S6k389, and Gsk3β9 decreased. In mechanism investigation, we found SHP2 membrane localization and phosphorylation level of SHP2542 elevated, which suggested SHP2 likely mediated the disruption.