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J. Biol. Chem., Vol. 278, Issue 42, 40806-40814, October 17, 2003

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Lipid-dependent Recruitment of Neuronal Src to Lipid Rafts in the Brain^*

Abir Mukherjee , Lionel Arnaud and Jonathan A. Cooper 

From the Fred Hutchinson Cancer Research Center, Seattle, Washington 98109

Although most Src family tyrosine kinases are modified by palmitoylation as well as myristoylation, Src itself is only myristoylated. Dual acylation is important for attachment to liquid-ordered microdomains or lipid rafts. Accordingly, Src is excluded from lipid rafts in fibroblasts. Evidence of partial genetic redundancy between Src and Fyn for brain-specific targets suggests that these two kinases may occupy overlapping subcellular locations. Neuronal Src (NSrc), an alternative isoform of Src with a 6-amino acid insert in the Src homology 3 domain, is highly expressed in neurons. We investigated whether this structural difference in NSrc allows it to associate with lipid rafts. We found that perinatal mouse brains express predominantly NSrc, which is partly (10–20%) in a lipid raft fraction from brain but not fibroblasts. The association of Src with brain lipid rafts does not depend on the NSrc insert but depends on the amino-terminal myristoylation signal. A crude lipid fraction from brain promotes NSrc entry into rafts in vitro. Moreover, lipid raft-localized NSrc is more catalytically active than NSrc from the soluble fraction, possibly because raft localization alters access to other tyrosine kinases and phosphatases. These findings suggest that NSrc may be involved in signaling from lipid rafts in mouse brain.

Received for publication, June 18, 2003 , and in revised form, August 5, 2003.

^* This work was supported by Grant R37-CA41072 from the NCI, National Institutes of Health. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Present address: Reproductive Endocrine Unit, Massachusetts General Hospital, 55 Fruit St., Boston, MA 02114.

To whom correspondence should be addressed: Fred Hutchinson Cancer Research Center, 1100 Fairview Ave. N, Mailstop A2-025, Seattle, WA 98109. Tel.: 206-667-4454; Fax: 206-667-6522; E-mail: jcooper{at}fhcrc.org.

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