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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

Authors

  • Hawash IY
  • Kesavan KP
  • Magee AI
  • Geahlen RL
  • Harrison ML

Journal

The Journal of biological chemistry

Publication Data

February 15, 2002

Associated Grants

  • Agency: NIGMS NIH HHS, Id: GM-48099

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