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PKA Regulates Shp2 Activity: A Role in Cardiac Hypertrophy

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posted on 21.10.2015, 00:00 authored by Brian T. Burmeister
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 2 (Shp2) is critical for cardiac function and mutations resulting in loss of Shp2 catalytic activity are associated with congenital cardiac defects and hypertrophy. I have identified a novel mechanism of Shp2 inhibition that may promote cardiac hypertrophy. I 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. I have identified two key amino acids in Shp2 that are phosphorylated by PKA. Utilizing double mutant PKA phospho-deficient (T73A/S189A) and phospho-mimetic (T73D/S189D) constructs, in vitro binding assays and phosphatase activity assays indicate that phosphorylation of these residues disrupts Shp2 interaction with tyrosine-phosphorylated substrates and inhibits its protein tyrosine phosphatase activity. Overall, my 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 cardiac hypertrophy.

History

Advisor

O'Bryan, John P.

Department

Pharmacology

Degree Grantor

University of Illinois at Chicago

Degree Level

Doctoral

Committee Member

Karginov, Andrei V. Minshall, Richard D. Skidgel, Randal A. Wolska, Beata M.

Submitted date

2015-08

Language

en

Issue date

21/10/2015

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