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Molecular and Cellular Biology, February 2000, p. 851-867, Vol. 20, No. 3
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

The Cbl Proto-Oncogene Product Negatively Regulates the Src-Family Tyrosine Kinase Fyn by Enhancing Its Degradation

Christopher E. Andoniou,1 Nancy L. Lill,1 Christine B. Thien,2 Mark L. Lupher Jr.,1,dagger Satoshi Ota,1 David D. L. Bowtell,3 Robin M. Scaife,2 Wallace Y. Langdon,2 and Hamid Band1,*

Lymphocyte Biology Section, Division of Rheumatology, Immunology and Allergy, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115,1 and Department of Pathology, University of Western Australia, Nedlands 6907, Western Australia,2 and Trescowithick Research Laboratories, Peter MacCallum Cancer Institute, Melborne 3000, Victoria,3 Australia

Received 13 January 1999/Returned for modification 22 March 1999/Accepted 28 October 1999

Fyn is a prototype Src-family tyrosine kinase that plays specific roles in neural development, keratinocyte differentiation, and lymphocyte activation, as well as roles redundant with other Src-family kinases. Similar to other Src-family kinases, efficient regulation of Fyn is achieved through intramolecular binding of its SH3 and SH2 domains to conserved regulatory regions. We have investigated the possibility that the tyrosine kinase regulatory protein Cbl provides a complementary mechanism of Fyn regulation. We show that Cbl overexpression in 293T embryonic kidney and Jurkat T-lymphocyte cells led to a dramatic reduction in the active pool of Fyn; this was seen as a reduction in Fyn autophosphorylation, reduced phosphorylation of in vivo substrates, and inhibition of transcription from a Src-family kinase response element linked to a luciferase reporter. Importantly, a Fyn mutant (FynY528F) relieved of intramolecular repression was still negatively regulated by Cbl. The Cbl-dependent negative regulation of Fyn did not appear to be mediated by inhibition of Fyn kinase activity but was correlated with enhanced protein turnover. Consistent with such a mechanism, elevated levels of Fyn protein were observed in cell lines derived from Cbl-/- mice compared to those in wild-type controls. The effects of Cbl on Fyn were not observed when the 70ZCbl mutant protein was analyzed. Taken together, these observations implicate Cbl as a component in the negative regulation of Fyn and potentially other Src-family kinases, especially following kinase activation. These results also suggest that protein degradation may be a general mechanism for Cbl-mediated negative regulation of activated tyrosine kinases.

* Corresponding author. Mailing address: Smith Building, Room 538C, One Jimmy Fund Way, Boston, MA 02115. Phone: (617) 525-1101. Fax: (617) 525-1010. E-mail: hband{at}rics.bwh.harvard.edu.

dagger Present address: ICOS Corp., Bothell, WA 98021.

Molecular and Cellular Biology, February 2000, p. 851-867, Vol. 20, No. 3
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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