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J. Biol. Chem., Vol. 276, Issue 16, 12667-12674, April 20, 2001
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From the Department of Pathology, Centre Medical Universitaire, 1 Rue Michel-Servet, 1211 Geneva 4, Switzerland
Stem cell factor (also known as mast cell
growth factor and kit-ligand) is a transmembrane growth factor with a
highly conserved cytoplasmic domain. Basolateral membrane expression in
epithelia and persistent cell surface exposure of stem cell factor are
required for complete biological activity in pigmentation, fertility,
learning, and hematopoiesis. Here we show by site-directed mutagenesis
that the cytoplasmic domain of stem cell factor contains a monomeric leucine-dependent basolateral targeting signal. N-terminal
to this motif, a cluster of acidic amino acids serves to increase the
efficiency of basolateral sorting mediated by the leucine residue.
Hence, basolateral targeting of stem cell factor requires a
mono-leucine determinant assisted by a cluster of acidic amino acids.
This mono-leucine determinant is functionally conserved in
colony-stimulating factor-1, a transmembrane growth factor related to
stem cell factor. Furthermore, this leucine motif is not capable of
inducing endocytosis, allowing for persistent cell surface expression
of stem cell factor. In contrast, the mutated cytoplasmic tail found in
the stem cell factor mutant MgfSl17H
induces constitutive endocytosis by a motif that is related to signals for endocytosis and lysosomal targeting. Our findings therefore
present mono-leucines as a novel type of protein sorting motif for
transmembrane growth factors.
Stem Cell Factor Presentation to c-Kit
IDENTIFICATION OF A BASOLATERAL TARGETING DOMAIN*
and
*
This work was supported by the Swiss National Science
Foundation Grants 31-52727-97 (to B. W.-H.) and 31-49241-96 (to
B. A. I.).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.
To whom correspondence should be addressed. Tel.:
41-22-702-5735; Fax: 41-22-702-5746; E-mail:
Bernhard.Wehrle-Haller@medecine.unige.ch.
Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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