| http://purl.uniprot.org/citations/25802336 | http://www.w3.org/1999/02/22-rdf-syntax-ns#type | http://purl.uniprot.org/core/Journal_Citation |
| http://purl.uniprot.org/citations/25802336 | http://www.w3.org/2000/01/rdf-schema#comment | "Pathological cardiac hypertrophy (an increase in cardiac mass resulting from stress-induced cardiac myocyte growth) is a major factor underlying heart failure. Src homology 2 domain-containing phosphatase (Shp2) is critical for cardiac function because mutations resulting in loss of Shp2 catalytic activity are associated with congenital cardiac defects and hypertrophy. We identified a novel mechanism of Shp2 inhibition that may promote cardiac hypertrophy. We demonstrate that Shp2 is a component of the protein kinase A anchoring protein (AKAP)-Lbc complex. AKAP-Lbc facilitates PKA phosphorylation of Shp2, which inhibits Shp2 phosphatase activity. We identified two key amino acids in Shp2 that are phosphorylated by PKA. Thr-73 contributes a helix cap to helix αB within the N-terminal SH2 domain of Shp2, whereas Ser-189 occupies an equivalent position within the C-terminal SH2 domain. Utilizing double mutant PKA phosphodeficient (T73A/S189A) and phosphomimetic (T73D/S189D) constructs, in vitro binding assays, and phosphatase activity assays, we demonstrate that phosphorylation of these residues disrupts Shp2 interaction with tyrosine-phosphorylated ligands and inhibits its protein-tyrosine phosphatase activity. Overall, our data indicate that AKAP-Lbc integrates PKA and Shp2 signaling in the heart and that AKAP-Lbc-associated Shp2 activity is reduced in hypertrophic hearts in response to chronic β-adrenergic stimulation and PKA activation. Therefore, although induction of cardiac hypertrophy is a multifaceted process, inhibition of Shp2 activity through AKAP-Lbc-anchored PKA is a previously unrecognized mechanism that may promote this compensatory response."xsd:string |
| http://purl.uniprot.org/citations/25802336 | http://purl.org/dc/terms/identifier | "doi:10.1074/jbc.m115.642983"xsd:string |
| http://purl.uniprot.org/citations/25802336 | http://purl.uniprot.org/core/author | "Wang L."xsd:string |
| http://purl.uniprot.org/citations/25802336 | http://purl.uniprot.org/core/author | "Skidgel R.A."xsd:string |
| http://purl.uniprot.org/citations/25802336 | http://purl.uniprot.org/core/author | "Burmeister B.T."xsd:string |
| http://purl.uniprot.org/citations/25802336 | http://purl.uniprot.org/core/author | "Carnegie G.K."xsd:string |
| http://purl.uniprot.org/citations/25802336 | http://purl.uniprot.org/core/author | "Gold M.G."xsd:string |
| http://purl.uniprot.org/citations/25802336 | http://purl.uniprot.org/core/author | "O'Bryan J.P."xsd:string |
| http://purl.uniprot.org/citations/25802336 | http://purl.uniprot.org/core/date | "2015"xsd:gYear |
| http://purl.uniprot.org/citations/25802336 | http://purl.uniprot.org/core/name | "J Biol Chem"xsd:string |
| http://purl.uniprot.org/citations/25802336 | http://purl.uniprot.org/core/pages | "12058-12067"xsd:string |
| http://purl.uniprot.org/citations/25802336 | http://purl.uniprot.org/core/title | "Protein Kinase A (PKA) Phosphorylation of Shp2 Protein Inhibits Its Phosphatase Activity and Modulates Ligand Specificity."xsd:string |
| http://purl.uniprot.org/citations/25802336 | http://purl.uniprot.org/core/volume | "290"xsd:string |
| http://purl.uniprot.org/citations/25802336 | http://www.w3.org/2004/02/skos/core#exactMatch | http://purl.uniprot.org/pubmed/25802336 |
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