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Mol Cell Biol, August 1998, p. 4872-4882, Vol. 18, No. 8
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

Tissue Hyperplasia and Enhanced T-Cell Signalling via ZAP-70 in c-Cbl-Deficient Mice

Maria A. Murphy,1 Ralf G. Schnall,1 Deon J. Venter,1 2 Louise Barnett,3 Ivan Bertoncello,1 Christine B. F. Thien,4 Wallace Y. Langdon,4 and David D. L. Bowtell1 *

Trescowthick Research Laboratories, Peter MacCallum Cancer Institute, Melbourne 3000,1 Department of Pathology, University of Melbourne,2 and The Walter and Eliza Hall Institute of Medical Research, The Royal Melbourne Hospital,3, Parkville 3050, Victoria, and Department of Pathology, University of Western Australia, Nedlands 6907, Western Australia,4 Australia

Received 17 February 1998/Returned for modification 16 April 1998/Accepted 5 May 1998

The c-Cbl protein is tyrosine phosphorylated and forms complexes with a wide range of signalling partners in response to various growth factors. How c-Cbl interacts with proteins, such as Grb2, phosphatidylinositol 3-kinase, and phosphorylated receptors, is well understood, but its role in these complexes is unclear. Recently, the Caenorhabditis elegans Cbl homolog, Sli-1, was shown to act as a negative regulator of epidermal growth factor receptor signalling. This finding forced a reassessment of the role of Cbl proteins and highlighted the desirability of testing genetically whether c-Cbl acts as a negative regulator of mammalian signalling. Here we investigate the role of c-Cbl in development and homeostasis in mice by targeted disruption of the c-Cbl locus. c-Cbl-deficient mice were viable, fertile, and outwardly normal in appearance. Bone development and remodelling also appeared normal in c-Cbl mutants, despite a previously reported requirement for c-Cbl in osteoclast function. However, consistent with a high level of expression of c-Cbl in the hemopoietic compartment, c-Cbl-deficient mice displayed marked changes in their hemopoietic profiles, including altered T-cell receptor expression, lymphoid hyperplasia, and primary splenic extramedullary hemopoiesis. The mammary fat pads of mutant female mice also showed increased ductal density and branching compared to those of their wild-type littermates, indicating an unanticipated role for c-Cbl in regulating mammary growth. Collectively, the hyperplastic histological changes seen in c-Cbl mutant mice are indicative of a normal role for c-Cbl in negatively regulating signalling events that control cell growth. Consistent with this view, we observed greatly increased intracellular protein tyrosine phosphorylation in thymocytes following CD3epsilon cross-linking. In particular, phosphorylation of ZAP-70 kinase in thymocytes was uncoupled from a requirement for CD4-mediated Lck activation. This study provides the first biochemical characterization of any organism that is deficient in a member of this unique protein family. Our findings demonstrate critical roles for c-Cbl in hemopoiesis and in controlling cellular proliferation and signalling by the Syk/ZAP-70 family of protein kinases.

* Corresponding author. Mailing address: Research Division, Peter MacCallum Cancer Institute, Locked Bag 1 A'Beckett St., Melbourne 3000, VIC, Australia. Phone: 61-3-96561296. Fax: 61-3-96561411. E-mail: d.bowtell{at}pmci.unimelb.edu.au.

Mol Cell Biol, August 1998, p. 4872-4882, Vol. 18, No. 8
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


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