The A-kinase-anchoring protein AKAP-Lbc facilitates cardioprotective PKA phosphorylation of Hsp20 on Ser(16).
Hsp20 (heat-shock protein of 20 kDa; HspB6) is a cardioprotective agent which combats a number of pathophysiological processes in the heart, including hypertrophy, apoptosis and ischaemia/reperfusion injury. The cardioprotective actions of Hsp20 require its phosphorylation by PKA (cAMP-dependent protein kinase) on Ser(16). Although the extracellular stimuli that promote cAMP-responsive phosphorylation of Hsp20 are well known, less is understood about the molecular processes that regulate this modification. AKAPs (A-kinase-anchoring proteins) physically compartmentalize PKA to specific locations within a cell to both direct PKA phosphorylation toward selected substrates and to orchestrate downstream signalling events. In the present study we used PKA anchoring disruptor peptides to verify that an AKAP underpins the cardioprotective phosphorylation of Hsp20. Biochemical and immunofluorescence techniques identify the cytosolic protein AKAP-Lbc (AKAP13) as the anchoring protein responsible for directing PKA phosphorylation of Hsp20 on Ser(16). Gene silencing and rescue experiments establish that AKAP-Lbc-mediated PKA phosphorylation of Hsp20 is crucial to the anti-apoptotic effects of the Hsp. Thus AKAP-Lbc may serve an ancillary cardioprotective role by favouring the association of PKA with Hsp20.
Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow G12 8QQ, UK.
Helen V
HV
Edwards
John D
JD
Scott
George S
GS
Baillie
D054758:A Kinase Anchor Proteins / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D050886:HSP20 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D015778:Minor Histocompatibility Antigens; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D012694:Serine / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction
D054758:A Kinase Anchor Proteins; C085467:AKAP13 protein, human; D050886:HSP20 Heat-Shock Proteins; C494382:HSPB6 protein, human; D015778:Minor Histocompatibility Antigens; D011518:Proto-Oncogene Proteins; D012694:Serine