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Negative regulation of Lck by Cbl ubiquitin ligase

By Navin Rao, Sachiko Miyake, Alagarsamy Lakku Reddi, Patrice Douillard, Amiya K. Ghosh, Ingrid L. Dodge, Pengcheng Zhou, Norvin D. Fernandes and Hamid Band

Abstract

The Cbl-family ubiquitin ligases function as negative regulators of activated receptor tyrosine kinases by facilitating their ubiquitination and subsequent targeting to lysosomes. Cbl associates with the lymphoid-restricted nonreceptor tyrosine kinase Lck, but the functional relevance of this interaction remains unknown. Here, we demonstrate that T cell receptor and CD4 coligation on human T cells results in enhanced association between Cbl and Lck, together with Lck ubiquitination and degradation. A Cbl−/− T cell line showed a marked deficiency in Lck ubiquitination and increased levels of kinase-active Lck. Coexpression in 293T cells demonstrated that Lck kinase activity and Cbl ubiquitin ligase activity were essential for Lck ubiquitination and negative regulation of Lck-dependent serum response element-luciferase reporter activity. The Lck SH3 domain was pivotal for Cbl-Lck association and Cbl-mediated Lck degradation, with a smaller role for interactions mediated by the Cbl tyrosine kinase-binding domain. Finally, analysis of a ZAP-70-deficient T cell line revealed that Cbl inhibited Lck-dependent mitogen-activated protein kinase activation, and an intact Cbl RING finger domain was required for this functional effect. Our results demonstrate a direct, ubiquitination-dependent, negative regulatory role of Cbl for Lck in T cells, independent of Cbl-mediated regulation of ZAP-70

Topics: Biological Sciences
Publisher: The National Academy of Sciences
Year: 2002
DOI identifier: 10.1073/pnas.062055999
OAI identifier: oai:pubmedcentral.nih.gov:122603
Provided by: PubMed Central
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