Focal adhesion kinase and p130Cas mediate both sarcomeric organization and activation of genes associated with cardiac myocyte hypertrophy.
Hypertrophic terminally differentiated cardiac myocytes show increased sarcomeric organization and altered gene expression. Previously, we established a role for the nonreceptor tyrosine kinase Src in signaling cardiac myocyte hypertrophy. Here we report evidence that p130Cas (Cas) and focal adhesion kinase (FAK) regulate this process. In neonatal cardiac myocytes, tyrosine phosphorylation of Cas and FAK increased upon endothelin (ET) stimulation. FAK, Cas, and paxillin were localized in sarcomeric Z-lines, suggesting that the Z-line is an important signaling locus in these cells. Cas, alone or in cooperation with Src, modulated basal and ET-stimulated atrial natriuretic peptide (ANP) gene promoter activity, a marker of cardiac hypertrophy. Expression of the C-terminal focal adhesion-targeting domain of FAK interfered with localization of endogenous FAK to Z-lines. Expression of the Cas-binding proline-rich region 1 of FAK hindered association of Cas with FAK and impaired the structural stability of sarcomeres. Collectively, these results suggest that interaction of Cas with FAK, together with their localization to Z-lines, is critical to assembly of sarcomeric units in cardiac myocytes in culture. Moreover, expression of the focal adhesion-targeting and/or the Cas-binding proline-rich regions of FAK inhibited ANP promoter activity and suppressed ET-induced ANP and brain natriuretic peptide gene expression. In summary, assembly of signaling complexes that include the focal adhesion proteins Cas, FAK, and paxillin at Z-lines in the cardiac myocyte may regulate, either directly or indirectly, both cytoskeletal organization and gene expression associated with cardiac myocyte hypertrophy.
Kovacic-Milivojević
B
B
Metabolic Research Unit, University of California San Francisco, San Francisco, California 94143-0540, USA.
Roediger
F
F
Almeida
E A
EA
Damsky
C H
CH
Gardner
D G
DG
Ilić
D
D
D000818:Animals; D009320:Atrial Natriuretic Factor / Q000235:genetics; D006332:Cardiomegaly / Q000235:genetics / Q000378:metabolism*; D002458:Cell Fractionation; D002478:Cells, Cultured; D050719:Crk-Associated Substrate Protein; D016895:Culture Media, Serum-Free; D003598:Cytoskeletal Proteins / Q000378:metabolism; D016232:Endothelins / Q000378:metabolism / Q000494:pharmacology; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D015151:Immunoblotting; D007150:Immunohistochemistry; D008840:Microfilament Proteins / Q000378:metabolism; D009206:Myocardium / Q000166:cytology* / Q000378:metabolism; D018995:Myosin Heavy Chains / Q000378:metabolism; D051419:Paxillin; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D017434:Protein Structure, Tertiary; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D011506:Proteins; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D050717:Retinoblastoma-Like Protein p130; D012518:Sarcomeres / Q000187:drug effects / Q000502:physiology*; D015398:Signal Transduction; D000070876:Tensins; D019061:src-Family Kinases / Q000378:metabolism
C493843:Bcar1 protein, rat; D050719:Crk-Associated Substrate Protein; D016895:Culture Media, Serum-Free; D003598:Cytoskeletal Proteins; D016232:Endothelins; D008840:Microfilament Proteins; D051419:Paxillin; D010750:Phosphoproteins; D011506:Proteins; C496063:Pxn protein, rat; D011993:Recombinant Fusion Proteins; D050717:Retinoblastoma-Like Protein p130; D000070876:Tensins; C000603372:Tns1 protein, rat; D009320:Atrial Natriuretic Factor; D011505:Protein-Tyrosine Kinases; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; C496052:Ptk2 protein, rat; D019061:src-Family Kinases; D018995:Myosin Heavy Chains