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The Lck SH3 domain negatively regulates localization to lipid rafts through an interaction with c-Cbl.

Lck is a member of the Src family of protein-tyrosine kinases and is essential for T cell development and function. Lck is localized to the inner surface of the plasma membrane and partitions into lipid rafts via dual acylation on its N terminus. We have tested the role of Lck binding domains in regulating Lck localization to lipid rafts. A form of Lck containing a point mutation inactivating the SH3 domain (W97ALck) was preferentially localized to lipid rafts compared with wild type or SH2 domain-inactive (R154K) Lck when expressed in Lck-deficient J.CaM1 cells. W97ALck incorporated more of the radioiodinated version of palmitic acid, 16-[(125)I]iodohexadecanoic acid. Overexpression of c-Cbl, a ligand of the Lck SH3 domain, depleted Lck from lipid rafts in Jurkat cells. Additionally, Lck localization to lipid rafts was enhanced in c-Cbl-deficient T cells. The association of Lck with c-Cbl in vivo required a functional SH3 domain. These results suggest a model whereby the SH3 domain negatively regulates basal localization of Lck to lipid rafts via association with c-Cbl.

Pubmed ID: 11741956 RIS Download

Mesh terms: Animals | Cell Line | Chickens | DNA, Complementary | Electrophoresis, Polyacrylamide Gel | Green Fluorescent Proteins | Humans | Jurkat Cells | Luminescent Proteins | Lymphocyte Specific Protein Tyrosine Kinase p56(lck) | Membrane Microdomains | Microscopy, Fluorescence | Point Mutation | Precipitin Tests | Protein Binding | Protein Structure, Tertiary | Proto-Oncogene Proteins | Proto-Oncogene Proteins c-cbl | Transfection | Ubiquitin-Protein Ligases | src Homology Domains