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70Z/3 Cbl induces PLCγ1 activation in T lymphocytes via an alternate Lat- and Slp-76-independent signaling mechanism

Oncogene volume 22, pages 2493–2503 (2003)Cite this article

Abstract

The oncoprotein 70Z/3 Cbl signals in an autonomous fashion or through blockade of endogenous c-Cbl, a negative regulator of signaling. The mechanism of 70Z/3 Cbl-induced signaling was investigated by comparing the molecular requirements for 70Z/3 Cbl- and TCR-induced phospholipase Cγ1 (PLCγ1) activation. 70Z/3 Cbl-induced PLCγ1 tyrosine phosphorylation required, in addition to the PLCγ1 N-terminal SH2 domain, the C-terminal SH2 and SH3 domains that were dispensable for TCR-induced phosphorylation. Deletion of the leucine zipper of 70Z/3 Cbl did not eliminate 70Z/3 Cbl-induced PLCγ1 phosphorylation, suggesting that blockage of c-Cbl via dimerization with 70Z/3 Cbl cannot fully explain 70Z/3 Cbl activating characteristics. The complete elimination of PLCγ1 phosphorylation required deleting the SH3 domain-binding region of 70Z/3 Cbl, consistent with 70Z/3 Cbl binding the PLCγ1 SH3 domain. 70Z/3 Cbl-induced PLCγ1 phosphorylation required Zap-70, as for the TCR, and the tyrosine kinase binding domain of 70Z/3 Cbl, which binds Zap-70, but did not require PLCγ1 binding to Lat, a crucial interaction in TCR-induced PLCγ1 phosphorylation. Furthermore, 70Z/3 Cbl-induced activation of NFAT, a PLCγ1/Ca2+-dependent transcriptional event, required Zap-70, but was independent of Slp-76, an adapter required for TCR-induced NFAT activation. These results suggest that 70Z/3 Cbl and PLCγ1 form a TCR-, Lat- and Slp-76-independent complex that leads to PLCγ1 phosphorylation and activation.

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Abbreviations

BCR:

B-cell receptor

TCR:

T-cell receptor

PLCγ1:

phospholipase Cγ1

SH:

src-homology

TKB:

tyrosine kinase binding

EGF:

epidermal growth factor

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Acknowledgements

We thank Drs Stephen Kozlowski and Richard Janssen for critical review and discussion of the manuscript. We also thank Drs Robert Abraham, Gerald Crabtree, Lawrence Samelson, Jerome Van Leeuwen, Ronald Wange, Arthur Weiss, and Allan Weissman for their gifts of reagents and cell lines.

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Author notes

  1. Cristiana Noviello and Rashmi Rawat: Supported in part by an appointment to the Research Participation Program at the Center for Biologics Evaluation and Research administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the US Department of Energy and the US Food and Drug Administration.

  2. Sandy Jen: Supported by the Foundation for Advanced Education in Sciences through a grant from the Howard Hughes Medical Institute.

Authors and Affiliations

  1. Division of Monoclonal Antibodies, Laboratory of Immunobiology, Center for Biologics Evaluation and Research, Bethesda, 20892, MD, USA

    Laurie J Graham, Maria-Concetta Verí, Karen E DeBell, Cristiana Noviello, Rashmi Rawat, Sandy Jen, Ezio Bonvini & Barbara Rellahan

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  1. Laurie J Graham
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Correspondence to Ezio Bonvini.

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Graham, L., Verí, MC., DeBell, K. et al. 70Z/3 Cbl induces PLCγ1 activation in T lymphocytes via an alternate Lat- and Slp-76-independent signaling mechanism. Oncogene 22, 2493–2503 (2003). https://doi.org/10.1038/sj.onc.1206318

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