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  • Original Paper
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Caspase-dependent cleavage of the hematopoietic specific adaptor protein Gads alters signalling from the T cell receptor

Oncogene volume 20, pages 1203–1211 (2001)Cite this article

Abstract

Gads is a SH2 and SH3 domain-containing, hematopoietic-specific adaptor protein that functions in signalling from the T cell receptor. Gads acts by linking SLP-76, bound by the carboxy-terminal Gads SH3 domain, to tyrosine phosphorylated LAT which contains binding sites for the Gads SH2 domain. Gads is distinguished from Grb2 and the closely related Grap protein by the presence of a 120 amino acid unique region between the SH2 domain and the carboxy terminal SH3 domain. Here we demonstrate that the unique region of Gads contains a capase cleavage site. Induction of apoptosis in lymphocytes results in detectable Gads cleavage by 60 min. Gads cleavage is blocked in vivo by treating cells with a caspase 3 inhibitor. A putative caspase 3 cleavage site was identified within the unique region and mutation of this site prevented Gads cleavage in vitro, and in vivo. The Gads cleavage products retained the predicted binding specificity for SLP-76 and LAT. Expression of the Gads cleavage products in Jurkat T cells inhibited NFAT activation following TCR cross linking. These findings indicate that cleavage of Gads in vivo could function to alter signalling downstream of the T cell receptor by disrupting cross talk between SLP-76 and LAT.

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Acknowledgements

The authors thank Dr Stan Liu for lively discussions, Dr Gary Koretzky for anti-SLP-76 and anti-SLAP-130 antiserum and Dr Ian Clarke for isolating primary lymphocytes. This work was funded by operating grants from the Cancer Research Society and from the Medical Research Council of Canada to CJ McGlade. SJ Benn is supported by a Natural Science and Engineering Research Council Fellowship. CJ McGlade is a Research Scientist of the National Cancer Institute of Canada supported with funds from the Canadian Cancer Society.

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  1. The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, M5G 1X8, Ontario, Canada

    Donna M Berry, Sally J Benn & C Jane McGlade

  2. Division of Rheumatology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA

    Alec M Cheng

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Berry, D., Benn, S., Cheng, A. et al. Caspase-dependent cleavage of the hematopoietic specific adaptor protein Gads alters signalling from the T cell receptor. Oncogene 20, 1203–1211 (2001). https://doi.org/10.1038/sj.onc.1204218

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