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

Overview

Journal J Cardiovasc Transl Res

Publisher Springer

Specialty Cardiology & Vascular Diseases

Date 2023 Mar 29

PMID 36988860

Authors

Hongmei Luo

Zhongzhou Yang

Jie Li

Hengwei Jin

Mingyang Jiang

Congjia Shan

Affiliations

Soon will be listed here.

Abstract

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.

References

Vincent S, Buckingham M . How to make a heart: the origin and regulation of cardiac progenitor cells. Curr Top Dev Biol. 2010; 90:1-41. DOI: 10.1016/S0070-2153(10)90001-X. View

Dyer L, Kirby M . The role of secondary heart field in cardiac development. Dev Biol. 2009; 336(2):137-44. PMC: 2794420. DOI: 10.1016/j.ydbio.2009.10.009. View

Bruneau B . The developmental genetics of congenital heart disease. Nature. 2008; 451(7181):943-8. DOI: 10.1038/nature06801. View

Plein A, Calmont A, Fantin A, Denti L, Anderson N, Scambler P . Neural crest-derived SEMA3C activates endothelial NRP1 for cardiac outflow tract septation. J Clin Invest. 2015; 125(7):2661-76. PMC: 4563681. DOI: 10.1172/JCI79668. View

Harmon A, Nakano A . Nkx2-5 lineage tracing visualizes the distribution of second heart field-derived aortic smooth muscle. Genesis. 2013; 51(12):862-9. PMC: 3943338. DOI: 10.1002/dvg.22721. View

Sawada H, Rateri D, Moorleghen J, Majesky M, Daugherty A . Smooth Muscle Cells Derived From Second Heart Field and Cardiac Neural Crest Reside in Spatially Distinct Domains in the Media of the Ascending Aorta-Brief Report. Arterioscler Thromb Vasc Biol. 2017; 37(9):1722-1726. PMC: 5570666. DOI: 10.1161/ATVBAHA.117.309599. View

Alessi D, Deak M, Casamayor A, Caudwell F, Morrice N, Norman D . 3-Phosphoinositide-dependent protein kinase-1 (PDK1): structural and functional homology with the Drosophila DSTPK61 kinase. Curr Biol. 1997; 7(10):776-89. DOI: 10.1016/s0960-9822(06)00336-8. View

Yang K, Shin S, Piao L, Shin E, Li Y, Park K . Regulation of 3-phosphoinositide-dependent protein kinase-1 (PDK1) by Src involves tyrosine phosphorylation of PDK1 and Src homology 2 domain binding. J Biol Chem. 2007; 283(3):1480-1491. DOI: 10.1074/jbc.M706361200. View

Lauriol J, Jaffre F, Kontaridis M . The role of the protein tyrosine phosphatase SHP2 in cardiac development and disease. Semin Cell Dev Biol. 2014; 37:73-81. PMC: 4339543. DOI: 10.1016/j.semcdb.2014.09.013. View

10.

Hof P, Pluskey S, Eck M, Shoelson S . Crystal structure of the tyrosine phosphatase SHP-2. Cell. 1998; 92(4):441-50. DOI: 10.1016/s0092-8674(00)80938-1. View

11.

Neel B, Gu H, Pao L . The 'Shp'ing news: SH2 domain-containing tyrosine phosphatases in cell signaling. Trends Biochem Sci. 2003; 28(6):284-93. DOI: 10.1016/S0968-0004(03)00091-4. View

12.

Araki T, Chan G, Newbigging S, Morikawa L, Bronson R, Neel B . Noonan syndrome cardiac defects are caused by PTPN11 acting in endocardium to enhance endocardial-mesenchymal transformation. Proc Natl Acad Sci U S A. 2009; 106(12):4736-41. PMC: 2649209. DOI: 10.1073/pnas.0810053106. View

13.

Moses K, DeMayo F, Braun R, Reecy J, Schwartz R . Embryonic expression of an Nkx2-5/Cre gene using ROSA26 reporter mice. Genesis. 2002; 31(4):176-80. DOI: 10.1002/gene.10022. View

14.

Verzi M, McCulley D, De Val S, Dodou E, Black B . The right ventricle, outflow tract, and ventricular septum comprise a restricted expression domain within the secondary/anterior heart field. Dev Biol. 2005; 287(1):134-45. DOI: 10.1016/j.ydbio.2005.08.041. View

15.

Yuan B, Wan P, Chu D, Nie J, Cao Y, Luo W . A cardiomyocyte-specific Wdr1 knockout demonstrates essential functional roles for actin disassembly during myocardial growth and maintenance in mice. Am J Pathol. 2014; 184(7):1967-80. DOI: 10.1016/j.ajpath.2014.04.007. View

16.

Lawlor M, Mora A, Ashby P, Williams M, Murray-Tait V, Malone L . Essential role of PDK1 in regulating cell size and development in mice. EMBO J. 2002; 21(14):3728-38. PMC: 126129. DOI: 10.1093/emboj/cdf387. View

17.

Zhu X, Shi D, Li X, Gong W, Wu F, Guo X . TLR signalling affects sperm mitochondrial function and motility via phosphatidylinositol 3-kinase and glycogen synthase kinase-3α. Cell Signal. 2015; 28(3):148-156. DOI: 10.1016/j.cellsig.2015.12.002. View

18.

Lyons I, Parsons L, Hartley L, Li R, Andrews J, Robb L . Myogenic and morphogenetic defects in the heart tubes of murine embryos lacking the homeo box gene Nkx2-5. Genes Dev. 1995; 9(13):1654-66. DOI: 10.1101/gad.9.13.1654. View

19.

Zhang L, Nomura-Kitabayashi A, Sultana N, Cai W, Cai X, Moon A . Mesodermal Nkx2.5 is necessary and sufficient for early second heart field development. Dev Biol. 2014; 390(1):68-79. PMC: 4461860. DOI: 10.1016/j.ydbio.2014.02.023. View

20.

Jin H, Wang H, Li J, Yu S, Xu M, Qiu Z . Differential contribution of the two waves of cardiac progenitors and their derivatives to aorta and pulmonary artery. Dev Biol. 2019; 450(2):82-89. DOI: 10.1016/j.ydbio.2019.03.019. View