Requirements for the localization of p130 Cas to Z-lines in cardiac myocytes.

The vertebrate heart responds to hemodynamic load with the enlargement of postmitotic, terminally differentiated cardiac myocytes. Such hypertrophic changes are characterized by alterations in sarcomeric organization and gene expression. Previously, we established a role for a nonreceptor tyrosine kinase, focal adhesion kinase, in signaling the changes in cytoskeletal organization associated with hypertrophy. Here, we report on data supporting a key role for p130Cas in this process. In neonatal cardiac myocytes FAK, Cas and paxillin are located in sarcomeric Z-lines, suggesting that the Z-line is an important signaling locus in these cells. The expression of different Cas mutants results in a nearly complete loss of sarcomeric organization in these myocytes. Moreover, expression of the C-terminal focal adhesion-targeting domain of FAK both disrupted sarcomeric organization and interfered with the localization of endogenous Cas to Z-lines. These findings suggest that the association of FAK and Cas and the preservation of multiple protein-interaction motifs of Cas are required for the correct assembly of sarcomeres in cardiac myocytes.