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J. Biol. Chem., Vol. 279, Issue 53, 55545-55555, December 31, 2004

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A Specific Endoplasmic Reticulum Export Signal Drives Transport of Stem Cell Factor (Kitl) to the Cell Surface^*

Frédérique Paulhe, Beat A. Imhof, and Bernhard Wehrle-Haller

From the Department of Pathology and Immunology, Centre Medical Universitaire, 1 rue Michel Servet, 1211 Geneva 4, Switzerland

Stem cell factor, also known as Kit ligand (Kitl), belongs to the family of dimeric transmembrane growth factors. Efficient cell surface presentation of Kitl is essential for the migration, proliferation, and survival of melanocytes, germ cells, hemopoietic stem cells, and mastocytes. Here we demonstrate that intracellular transport of Kitl to the cell surface is driven by a motif in the cytoplasmic tail that acts independently of the previously described basolateral sorting signal. Transport of Kitl to the cell surface is controlled at the level of the endoplasmic reticulum (ER) and requires a C-terminal valine residue positioned at a distance of 19–36 amino acids from the border between the transmembrane and cytoplasmic domains. Deletion or substitution of the valine with other hydrophobic amino acids results in ER accumulation and reduced cell surface transport of Kitl at physiological expression levels. When these mutant proteins are overexpressed in the ER, they are transported by bulk flow to the cell surface albeit at lower efficiency. A fusion construct between Kitl and the green fluorescent protein-labeled extracellular domain of a temperature-sensitive mutant of vesicular stomatitis virus G protein revealed the valine-dependent recruitment into coat protein complex II-coated ER exit sites and vesicular ER to Golgi transport in living cells. Thus the C-terminal valine defines a specific ER export signal in Kitl. It is responsible for the capture of Kitl at coat protein complex II-coated ER exit sites, leading to subsequent cell surface transport under physiological conditions.

Received for publication, July 12, 2004 , and in revised form, September 15, 2004.

^* This work was supported in part by a grant from the INSERM (to F. P.) and by grants from the Swiss National Science Foundation (31-49241.96, 31-052727.97, 31-059173.99, 31-64000.00, and 5894.1KTS) (to B. A. I. and B. W.-H.). 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.

The on-line version of this article (available at http://www.jbc.org) contains videos 1–6.

To whom correspondence should be addressed. Tel.: 41-22-379-5764; Fax: 41-22-379-5746; E-mail: Bernhard.Wehrle-Haller{at}medecine.unige.ch.

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