Peter Besmer: Roles of Soluble and Membrane Kit-Ligand In Vivo

Membrane growth factors that are processed to produce soluble ligands may function both as soluble factors and as membrane factors. Important questions concerning membrane growth factors include the role of soluble and membrane forms in vivo and the elucidation of mechanisms governing their production.

The membrane growth factor Kit-Ligand (KL), the ligand of the Kit receptor tyrosine kinase, is encoded at the Sl locus, and mice carrying Sl mutations have defects in hematopoiesis, gametogenesis, and melanogenesis. Two alternatively spliced KL transcripts encode 2 cell-associated KL protein products, KL-1 and KL-2. The KL-2 protein lacks the major proteolytic cleavage site for the generation of soluble KL, thus representing a more stable cell-associated form of KL.

We are using various knock-in mouse models to define the functional significance of KL-1 and KL-2. Thus we are generating mice that exclusively express either KL-1, KL-2, or membrane obligatory forms thereof. At this time, we have characterized the phenotypes of mice producing exclusively KL-2. Our results indicate that KL-2 may substitute for KL-1 in most situations, with the exception of the production of mast cells; and induced proteolytic cleavage of KL-1 to produce soluble KL may have a role in the regeneration of hematopoietic tissue after radiation injury. In addition, we are attempting to elucidate the mechanism of proteolytic processing of the KL-1 and KL-2 proteins.