CARDIOVASCULAR ANOMALY, IMPAIRED ACTIN BUNDLING AND RESISTANCE TO SRC-INDUCED TRANSFORMATION IN MICE LACKING P130(CAS)

p130(Cas) (Cas), the protein encoded by the Crkas gene (also known as Gas), is an adaptor molecule with a unique structure that contains a S rc homology (SH)-3 domain followed by multiple YXXP motifs and a proli ne-rich region(1). Cas was originally cloned as a highly tyrosine-phos phorylated protein in cells transformed by v-Src (refs 2,3) or v-Crk ( ref, 4) and has subsequently been implicated in a variety of biologica l processes including cell adhesion(5), cell migration(6), growth fact or stimulation(7-9), cytokine receptor engagement(10,11) and bacterial infection(12,13). To determine its role in vivo, we generated mice la cking Gas. Cas-deficient embryos died in utero showing marked systemic congestion and growth retardation. Histologically, the heart was poor ly developed and blood vessels were prominently dilated. Electron micr oscopic analysis of the heart revealed disorganization of myofibrils a nd disruption of Z-disks. In addition, actin stress fiber formation wa s severely impaired in Cas-deficient primary fibroblasts. Moreover, ex pression of activated Src in Cas-deficient primary fibroblasts did not induce a fully transformed phenotype, possibly owing to insufficient accumulation of actin cytoskeleton in podosomes. These findings have d efined Cas function in cardiovascular development, actin filament asse mbly and Src-induced transformation.