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

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