The role of the protein tyrosine phosphatase SHP2 in cardiac development and disease

Abstract

Congenital heart disease is the most common human developmental disorder, affecting ~1:100 newborns, and is the primary cause of birth-defect related deaths worldwide. As a major regulator of receptor tyrosine kinase (RTK), cytokine and G-protein coupled receptor signaling, the non-receptor protein tyrosine phosphatase SHP2 plays a critical role in normal cardiac development and function. Indeed, SHP2 participates in a wide variety of cellular functions, including proliferation, survival, differentiation, migration, and cell-cell communication. Moreover, human activating and inactivating mutations of SHP2 are responsible for two related developmental disorders called Noonan and LEOPARD Syndromes, respectively, which are both characterized, in part, by congenital heart defects. Structural, enzymologic, biochemical, and SHP2 mouse model studies have together greatly enriched our knowledge of SHP2 and, as such, have also uncovered the diverse roles for SHP2 in cardiac development, including its contribution to progenitor cell specification, cardiac morphogenesis, and maturation of cardiac valves and myocardial chambers. By delineating the precise mechanisms by which SHP2 is involved in regulating these processes, we can begin to better understand the pathogenesis of cardiac disease and find more strategic and effective therapies for treatment of patients with congenital heart disorders.

Rare copy number variants and congenital heart defects in the 22q11.2 deletion syndrome

“…This exact 12q24.13 duplication has not been reported in the non-syndromic CHD literature, but variants in PTPN11 have been associated with non-syndromic TOF (Cordell et al 2013; Goodship et al 2012). Furthermore, PTPN11 mutations are known to cause a spectrum of cardiac developmental defects, and are observed frequently in patients with Noonan syndrome and LEOPARD syndrome (Lauriol et al 2015; Sznajer et al 2007). …”

Paraspinal neurofibromas and hypertrophic neuropathy in Noonan syndrome with multiple lentigines

“…Thus, the molecular pathogenesis of the tumours in RASopathies, other than NF1, remains unknown. As a role of PTPN11 mutations is suggested in cardiac morphogenesis and hypertrophic cardiomyopathy,11 a similar mechanism may be responsible for the nerve overgrowth and formation of neurofibromas in NSML. There might also be an analogy with multiple giant cell lesions in RASopathies where extensive multilocular tumour development has been observed in a few cases with no strict correlation to the underlying germline mutation 17.…”

“…RAS-MAPK pathway has a critical role in cell proliferation, motility and death, regulation of morphology determination, organogenesis and growth1 11 Carcinogenic potential has been suggested in most of the RASopathies, but except for Costello syndrome, there are no surveillance programmes for patients with other RASopathies. Carriers of a PTPN11 constitutional mutation have a higher risk of cancer compared with the general population 9.…”

Modulation of VEGF receptor 2 signaling by protein phosphatases

“…Shp2 is a positive regulator of the Ras-ERK pathway and multiple limes of evidences indicate that Shp2 is upstream of RAS [114]. Indeed, removal of Shp2 impairs ERK activation downstream of various RTKs, integrins, and cytokines [97, 115, 116]. Finally, expression of Shp2 in the endothelium reduces baseline phosphorylation of junctional proteins (e.g.…”