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A‐kinase anchoring protein (AKAP)‐Lbc coordinates protein kinase A (PKA) phosphorylation and inhibition of Src homology 2 domain‐containing phosphatase 2 (Shp2)
Author(s) -
Burmeister Brian T.,
Taglieri Domenico M.,
Wang Li,
Carnegie Graeme K.
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.1031.2
Subject(s) - phosphorylation , protein kinase a , protein tyrosine phosphatase , phosphatase , proto oncogene tyrosine protein kinase src , medicine , cardiac myocyte , muscle hypertrophy , microbiology and biotechnology , endocrinology , kinase , chemistry , tyrosine phosphorylation , tyrosine kinase , protein phosphatase 1 , signal transduction , heart failure , biology
Pathological cardiac hypertrophy (an increase in cardiac mass resulting from stress‐induced cardiac myocyte growth) is a major factor underlying heart failure. Shp2 is a tyrosine phosphatase that is critical for cardiac function. Mutations resulting in loss of Shp2 catalytic activity are associated with cardiac hypertrophy and congenital heart defects. 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 PKA phosphorylation of Shp2, which 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 compensatory cardiac hypertrophy. We are currently mapping the PKA phosphorylation site(s) on Shp2 and investigating downstream hypertrophic signaling mechanisms.