A Physical Interaction between the Cell Death Protein Fas and the Tyrosine Kinase p59

doi:10.1074/jbc.271.11.5968

A Physical Interaction between the Cell Death Protein Fas and the Tyrosine Kinase p59(*)

From the (1)Departments of Biochemistry and
(2)Immunology, University of Alberta, Edmonton, Alberta, Canada T6G 2H7 and the
(3)Center for Immunology and Department of Pathology, Washington University School of Medicine, St. Louis, Missouri 63110

^§§Medical Scientist of the Alberta Heritage Foundation for Medical Research. To whom correspondence should be addressed. Tel.: 403-492-3968; Fax: 403-492-0886.

Abstract

The Fas antigen (Apo1/CD95) is a transmembrane protein belonging to the nerve growth factor receptor family. It is expressed on a variety of cells, including activated T lymphocytes. Ligation of Fas with its natural ligand or with anti-Fas antibodies often results in the apoptotic death of the cell, making Fas an important mediator of down-regulating immune responses. The signal transduction pathways utilized by Fas are currently unknown, although tyrosine kinase activity has recently been strongly implicated. Here, we report that the tyrosine kinase p59 physically associates with Fas in Fas-sensitive cells. In addition, we show that activated T lymphocytes from fyn knockout mice exhibit elevated lifespans and reduced apoptosis in vitro compared to their normal counterparts. Furthermore, activated T lymphocytes from the fyn- deficient mice are less sensitive to killing by both anti-Fas antibody and Fas-ligand cytotoxic T cells. These results suggest that p59 plays an important role in Fas signal transduction.

Footnotes

↵^§ Scholars of the Alberta Heritage Foundation for Medical Research.
↵^¶ Graduate Student of the Alberta Heritage Foundation for Medical Research.
↵** Postdoctoral Fellow of the Alberta Heritage Foundation for Medical Research.
↵* This work was supported in part by grants from the National Cancer Institute and Medical Research Council of Canada. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore by hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
↵¹ The abbreviations used are:

TNF

tumor necrosis factor

ITAM

immunoreceptor t yrosine-based activation motif

PMA

phorbol 12-myristate 13-acetate

MLC

mixed lymphocyte culture

PBS

phosphate-buffered saline.
↵²E. A. Atkinson and R. C. Bleackley, unpublished observations.
↵³E. A. Atkinson and R. C. Bleackley, personal observation.
- Received June 29, 1995.
- Revision received January 19, 1996.