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J. Biol. Chem., Vol. 277, Issue 7, 5683-5691, February 15, 2002
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From the 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-[125I]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.
The Lck SH3 Domain Negatively Regulates Localization to Lipid
Rafts through an Interaction with c-Cbl*
§,
, Departments of Biology and Medicinal
Chemistry and Molecular Pharmacology, Purdue University,
West Lafayette, Indiana 47907 and ¶ National Institute for
Medical Research, The Ridgeway, Mill Hill,
London NW7 1AA, United Kingdom
*
This work was supported by National Institutes of Health
Grant GM-48099 (to M. L. H.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Present address: Division of Biomedical Science, Imperial
College of Science, Technology and Medicine, London SW7 2AZ, UK.
**
To whom correspondence should be addressed: Dept. of Medicinal
Chemistry and Molecular Pharmacology, Hansen Life Sciences Bldg.,
Purdue University, West Lafayette, IN 47907. Tel.: 765-494-1442; Fax:
765-494-9193; E-mail: harrison@pharmacy.purdue.edu.
Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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