Stem cell factor presentation to c-kit - Identification of a basolateral targeting domain

Stem cell factor (also known as mast cell growth factor and kit-ligand) is a transmembrane growth factor with a highly conserved cytoplasmic domain. B asolateral membrane expression in epithelia and persistent cell surface exp osure 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 contai ns a monomeric leucine-dependent basolateral targeting signal. N-terminal t o this motif, a cluster of acidic amino acids serves to increase the effici ency of basolateral sorting mediated by the leucine residue. Hence, basolat eral targeting of stem cell factor requires a mono-leucine determinant assi sted by a cluster of acidic amino acids. This mono-leucine determinant is f unctionally conserved in colony-stimulating factor-1, a transmembrane growt h factor related to stem cell factor. Furthermore, this leucine motif is no t capable of inducing endocytosis, allowing for persistent cell surface exp ression of stem cell factor. In contrast, the mutated cytoplasmic tail foun d in the stem cell factor mutant Mgf(SI17H) induces constitutive endocytosi s by a motif that is related to signals for endocytosis and lysosomal targe ting. Our findings therefore present monoleucines as a novel type of protei n sorting motif for transmembrane growth factors.