Cardiovascular anomaly, impaired actin bundling and resistance to Src-induced transformation in mice lacking p130Cas.
p130Cas (Cas), the protein encoded by the Crkas gene (also known as Cas), is an adaptor molecule with a unique structure that contains a Src homology (SH)-3 domain followed by multiple YXXP motifs and a proline-rich region. Cas was originally cloned as a highly tyrosine-phosphorylated protein in cells transformed by v-Src (refs 2,3) or v-Crk (ref. 4) and has subsequently been implicated in a variety of biological processes including cell adhesion, cell migration, growth factor stimulation, cytokine receptor engagement and bacterial infection. To determine its role in vivo, we generated mice lacking Cas. Cas-deficient embryos died in utero showing marked systemic congestion and growth retardation. Histologically, the heart was poorly developed and blood vessels were prominently dilated. Electron microscopic analysis of the heart revealed disorganization of myofibrils and disruption of Z-disks. In addition, actin stress fiber formation was severely impaired in Cas-deficient primary fibroblasts. Moreover, expression 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 defined Cas function in cardiovascular development, actin filament assembly and Src-induced transformation.
Honda
H
H
Third Department of Internal Medicine, Faculty of Medicine, University of Tokyo, Japan.
Oda
H
H
Nakamoto
T
T
Honda
Z
Z
Sakai
R
R
Suzuki
T
T
Saito
T
T
Nakamura
K
K
Nakao
K
K
Ishikawa
T
T
Katsuki
M
M
Yazaki
Y
Y
Hirai
H
H
D008841:Actin Cytoskeleton / Q000473:pathology*; D000199:Actins / Q000096:biosynthesis; D000595:Amino Acid Sequence; D000818:Animals; D001808:Blood Vessels / Q000196:embryology / Q000473:pathology*; D002461:Cell Line, Transformed; D002471:Cell Transformation, Neoplastic; D002478:Cells, Cultured; D050719:Crk-Associated Substrate Protein; D005347:Fibroblasts; D006321:Heart / Q000196:embryology; D008099:Liver / Q000737:chemistry / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D009206:Myocardium / Q000473:pathology* / Q000648:ultrastructure; D015688:Oncogene Protein pp60(v-src) / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D010750:Phosphoproteins / Q000032:analysis / Q000502:physiology*; D010766:Phosphorylation; D011506:Proteins; D011993:Recombinant Fusion Proteins; D050717:Retinoblastoma-Like Protein p130; D012518:Sarcomeres
D000199:Actins; C493842:Bcar1 protein, mouse; D050719:Crk-Associated Substrate Protein; D010750:Phosphoproteins; D011506:Proteins; D011993:Recombinant Fusion Proteins; D050717:Retinoblastoma-Like Protein p130; D015688:Oncogene Protein pp60(v-src)