Burmeister, BT;
Wang, L;
Gold, MG;
Skidgel, RA;
O'Bryan, JP;
Carnegie, GK;
(2015)
Protein kinase A (PKA) phosphorylation of Shp2 inhibits its phosphatase activity and modulates ligand specificity.
J Biol Chem
, 290
pp. 12058-12067.
10.1074/jbc.M115.642983.
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Abstract
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 as mutations resulting in loss of Shp2 catalytic activity are associated with congenital cardiac defects and hypertrophy. We have identified a novel mechanism of Shp2 inhibition that may promote cardiac hypertrophy. We demonstrate that Shp2 is a component of the A-kinase anchoring protein (AKAP)-Lbc complex. AKAP-Lbc facilitates protein kinase A (PKA) phosphorylation of Shp2, which inhibits Shp2 phosphatase activity. We have identified two key amino acids in Shp2 that are phosphorylated by PKA: Thr73 contributes a helix-cap to helix αB within the N-terminal SH2 domain of Shp2, whereas Ser189 occupies an equivalent position within the C-terminal SH2 domain. Utilizing double mutant PKA phospho-deficient (T73A/S189A) and phospho-mimetic (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. Thus, while 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.
| Type: | Article |
|---|---|
| Title: | Protein kinase A (PKA) phosphorylation of Shp2 inhibits its phosphatase activity and modulates ligand specificity. |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1074/jbc.M115.642983 |
| Publisher version: | http://dx.doi.org/10.1074/jbc.M115.642983 |
| Additional information: | © 2015 by The American Society for Biochemistry and Molecular Biology, Inc. Author's Choice—Final version free via Creative Commons CC-BY license. |
| Keywords: | A-kinase anchoring protein (AKAP), cardiac hypertrophy, protein kinase A (PKA), signal transduction, tyrosine-protein phosphatase (tyrosine phosphatase) |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Neuro, Physiology and Pharmacology |
| URI: | https://discovery.ucl.ac.uk/id/eprint/1464327 |
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