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Cardiovascular anomaly, impaired actin bundling and resistance to Src-induced transformation in mice lacking p130Cas
1Third Department of Internal Medicine, Faculty of Medicine, University of Tokyo, Japan.
Abstract:
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.
Insights
The adaptor protein p130Cas (Cas) is essential for cardiovascular development and actin assembly. Mice lacking Cas die in utero due to severe developmental defects, highlighting its critical in vivo functions.
Area of Science:
- Molecular and Cellular Biology
- Developmental Biology
- Biochemistry
Background:
- p130Cas (Cas) is an adaptor protein involved in various cellular processes like adhesion and migration.
- Cas contains SH3 and proline-rich domains, and YXXP motifs, crucial for protein interactions.
- Its role in vivo was previously unclear, despite its implication in signaling pathways.
Purpose of the Study:
- To investigate the in vivo function of p130Cas (Cas) using genetically modified mice.
- To elucidate the role of Cas in cardiovascular development and actin cytoskeleton organization.
Main Methods:
- Generation of Cas-deficient mice.
- Histological and electron microscopic analysis of embryonic tissues.
- Assessment of actin stress fiber formation and Src-induced transformation in primary fibroblasts.
Main Results:
- Cas-deficient embryos exhibited embryonic lethality in utero with systemic congestion and growth retardation.
- Histological analysis revealed poorly developed hearts and dilated blood vessels.
- Impaired actin stress fiber formation and podosome accumulation were observed in Cas-deficient fibroblasts, hindering Src-induced transformation.
Conclusions:
- p130Cas (Cas) is indispensable for embryonic cardiovascular development.
- Cas plays a critical role in actin filament assembly and organization.
- The adaptor protein is essential for mediating Src-induced cellular transformation.