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

Phosphoinositide-dependent protein kinase-1 (PDK 1 ), a master kinase and involved in multiple signaling transduction, participates in regulating embryonic cardiac development and postnatal cardiac remodeling. Germline PDK 1 knockout mice displayed no heart development; in this article, we deleted PDK 1 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 PDK 1 with Nkx2.5-cre, the heart showed prominent pulmonic stenosis. Ablated PDK 1 with Mef2c SHF -cre, the second heart field (SHF) exhibited severe hypoplasia. And deleted PDK 1 with αMHC-cre, the mice displayed dilated heart disease, protein analysis indicated PI3K and ERK were activated; meanwhile, PDK 1 -AKT-GSK3, and S6K-S6 were disrupted; phosphorylation level of Akt 473 , S6k 421/424 , and Gsk3 α21 enhanced; however, Akt 308 , S6k 389 , and Gsk3 β9 decreased. In mechanism investigation, we found SHP 2 membrane localization and phosphorylation level of SHP2 542 elevated, which suggested SHP 2 likely mediated the disruption. Graphical abstract