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Cardiovascular anomaly, impaired actin bundling and resistance to Src-induced transformation in mice lacking p130Cas

Nature Genetics volume 19, pages 361–365 (1998)Cite this article

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 region1. 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 adhesion5, cell migration6, growth factor stimulation7,8,9, cytokine receptor engagement10,11 and bacterial infection12,13. 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.

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Figure 1: Targeted disruption of mouse Crkas.
Figure 2: Histopathological analyses of embryos.
Figure 3: Immunofluorescent analyses of primary fibroblasts.
Figure 4: Morphological, biochemical and immunofluorescent analyses of primary fibroblasts expressing a-Src.

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Acknowledgements

We thank E. Robertson for providing us with the CCE ES cells, S. Muroi and M. Tanaka for technical advice regarding the culture of ES cells and K. Katsuki for helpful comments. We also thank S. Iwasaka and Y. Oh-hira for preparing pathological specimens and N. Machiyama for photographs. This work was in part supported by Grants-in-Aids from the Ministry of Education, Science and Culture of Japan.

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Authors and Affiliations

  1. Third Department of Internal Medicine, Faculty of Medicine, University of Tokyo, 7-3-1 Hongo, Tokyo, 113, Bunkyo-ku, Japan

    Hiroaki Honda, Tetsuya Nakamoto, Ryuichi Sakai, Takahiro Suzuki, Toshiki Saito, Yoshio Yazaki & Hisamaru Hirai

  2. Department of Pathology, Faculty of Medicine, University of Tokyo, 7-3-1 Hongo, Tokyo , 113, Bunkyo-ku, Japan

    Hideaki Oda & Takatoshi Ishikawa

  3. Department of Internal Medicine and Physical Therapy, Faculty of Medicine, University of Tokyo, 7-3-1 Hongo, Tokyo, 113, Bunkyo-ku, Japan

    Zen-ichiro Honda

  4. Department of DNA Embryology, Institute of Medical Science, University of Tokyo, 4-6-1 Shiroganedai, Tokyo, 108, Minato-ku, Japan

    Kenji Nakamura, Kazuki Nakao & Motoya Katsuki

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Correspondence to Hisamaru Hirai.

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Honda, H., Oda, H., Nakamoto, T. et al. Cardiovascular anomaly, impaired actin bundling and resistance to Src-induced transformation in mice lacking p130Cas. Nat Genet 19, 361–365 (1998). https://doi.org/10.1038/1246

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