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Molecular and Cellular Biology, November 2003, p. 7708-7718, Vol. 23, No. 21
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.21.7708-7718.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Cbl-3-Deficient Mice Exhibit Normal Epithelial Development

Emily K. Griffiths,^1,2 Otto Sanchez,¹ Pleasantine Mill,³ Connie Krawczyk,^1,2 Carlo V. Hojilla,¹ Evelyn Rubin,¹ Marion M. Nau,⁴ Rama Khokha,¹ Stan Lipkowitz,⁴ Chi-chung Hui,³ and Josef M. Penninger^1,2*

Department of Medical Biophysics, Ontario Cancer Institute, University of Toronto, Toronto, Ontario, Canada M5G 2C1,¹ Institute for Molecular Biotechnology of the Austrian Academy of Sciences, A-1030 Vienna, Austria,² Program in Developmental Biology, The Hospital for Sick Children, and Department of Molecular and Medical Genetics, University of Toronto, Toronto, Ontario, Canada M5G 1X8,³ Regulation of Protein Function Laboratory, National Cancer Institute—Frederick, NIH, Frederick, Maryland 21702⁴

Received 23 January 2003/ Returned for modification 10 April 2003/ Accepted 23 July 2003

Cbl family proteins are evolutionarily conserved ubiquitin ligases that negatively regulate signaling from tyrosine kinase-coupled receptors. The mammalian cbl family consists of c-Cbl, Cbl-b, and the recently cloned Cbl-3 (also known as Cbl-c). In this study, we describe the detailed expression pattern of murine Cbl-3 and report the generation and characterization of Cbl-3-deficient mice. Cbl-3 exhibits an expression pattern distinct from those of c-Cbl and Cbl-b, with high levels of Cbl-3 expression in epithelial cells of the gastrointestinal tract and epidermis, as well as the respiratory, urinary, and reproductive systems. Cbl-3 expression was not detected in nonepithelial cells, but within epithelial tissues, the levels of Cbl-3 expression varied from undetectable in the alveoli of the lungs to very strong in the cecum and colon. Despite this restricted expression pattern, Cbl-3-deficient mice were viable, healthy, and fertile and displayed no histological abnormalities up to 18 months of age. Proliferation of epithelial cells in the epidermises and gastrointestinal tracts was unaffected by the loss of Cbl-3. Moreover, Cbl-3 was not required for attenuation of epidermal growth factor-stimulated Erk activation in primary keratinocytes. Thus, Cbl-3 is dispensable for normal epithelial development and function.

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* Corresponding author. Mailing address: IMBA, Institute for Molecular Biotechnology of the Austrian Academy of Sciences, c/o Dr. Bohr Gasse 7, A-1030 Vienna, Austria. Phone: 43-1-79730, ext. 454. Fax: 43-1-79730459. E-mail: josef.penninger{at}imba.oeaw.ac.at.

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Molecular and Cellular Biology, November 2003, p. 7708-7718, Vol. 23, No. 21
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.21.7708-7718.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

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