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Youichi Tajima^*, Eric J. Huang^*,, Keith Vosseller^*,, Masao Ono^*, Malcolm A.S. Moore, and Peter Besmer^*,

From the ^* Molecular Biology Program and Cell Biology Program, Memorial Sloan-Kettering Cancer Center, and Sloan-Kettering Division, Graduate School of Medical Sciences, Cornell University, New York 10021

The Kit ligand (KL)/Kit receptor pair functions in hematopoiesis, gametogenesis, and melanogenesis. KL is encoded at the murine steel (Sl) locus and encodes a membrane growth factor which may be proteolytically processed to produce soluble KL. The membrane-associated form of KL is critical in mediating Kit function in vivo. Evidence for a role of cytoplasmic domain sequences of KL comes from the Sl^17H mutation, a splice site mutation that replaces the cytoplasmic domain with extraneous amino acids. Using deletion mutants and the Sl^17H allele, we have investigated the role of the cytoplasmic domain sequences of KL in biosynthetic processing and cell surface presentation. The normal KL protein products are processed for cell surface expression, where they form dimers. Both Sl^17H and the cytoplasmic deletion mutants of KL were processed to the cell surface; however, the rate of transport and protein stability were affected by the mutations. Deletion of cytoplasmic domain sequences of KL did not affect dimerization of KL. In contrast, dimerization of the Sl^17H protein was reduced substantially. In addition, we have characterized the hematopoietic cell compartment in Sl^17H mutant mice. The Sl^17H mutation has only minor effects on hematopoiesis. Tissue and peritoneal mast cell numbers were reduced in mutant mice as well as in myeloid progenitors. Interestingly, long-term bone marrow cultures from Sl^17H mice did not sustain the long-term production of hematopoietic cells. In addition, homing of normal hematopoietic progenitors to the spleen of irradiated Sl^17H/Sl^17H recipient mice was diminished in transplantation experiments, providing evidence for a role of Kit in homing or lodging. These results demonstrate that the membrane forms of KL exist as homodimers on the cell surface and that dimerization may play an important role in KL/Kit-mediated juxtacrine signaling.

Support by grants from the American Cancer Society and the National Institutes of Health is acknowledged.

Abbreviations used: BFU-E, burst-forming unit–erythroid; BMMC, bone marrow–derived mast cell; CFU-GEMM, CFU-granulocyte erythroid megakaryocyte macrophage; CFU-S, CFU-spleen; endo, endoglycosidase; ER, endoplasmic reticulum; KL, Kit ligand; Sl, steel; VLA, very late antigen; W, white-spotting; WBC, white blood cell.

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