This Article
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Lev, S
Right arrow Articles by Yarden, Y
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Lev, S
Right arrow Articles by Yarden, Y

 Previous Article  |  Next Article 

Mol Cell Biol. 1993 April; 13(4): 2224-2234

Interspecies molecular chimeras of kit help define the binding site of the stem cell factor.

S Lev, J Blechman, S Nishikawa, D Givol and Y Yarden

Department of Chemical Immunology, Weizmann Institute of Science, Rehovot, Israel.

ABSTRACT

The extracellular portion of the kit-encoded receptor for the stem cell factor (SCF) comprises five immunoglobulin (Ig)-like domains. To localize the ligand recognition site, we exploited the lack of binding of human SCF to the murine receptor by using human-mouse hybrids of Kit and species-specific monoclonal antibodies (MAbs) that inhibit ligand binding. Replacement of the three N-terminal Ig-like domains of the murine Kit with the corresponding portion of the human receptor conferred upon the chimeric receptor high-affinity binding of the human ligand as well as of human-specific ligand-inhibitory MAbs. By constructing five chimeric murine Kit proteins which individually contain each of these three human Ig-like units or pairs of them, we found that the second human domain confers upon the mouse Kit high-affinity binding of the human ligand and also binding of species-specific SCF-competitive MAbs. Nevertheless, the flanking Ig-like domains also affect high-affinity recognition of SCF. Moreover, it appears that the determinants that define ligand specificity of the murine and the human receptors do not structurally coincide. This observation allowed us to identify a chimeric receptor that displayed a dual specificity; namely, it bound with high affinity either the human or the murine SCF molecules and reacted with mouse- as well as human-specific ligand-inhibitory MAbs. Conversely, another chimera, which included all of the five Ig-like domains, bound neither ligand. In conclusion, interdomain packing involving the second Ig-like domain of human Kit and noncontiguous structural motifs of the receptor are involved in SCF recognition.

Mol Cell Biol. 1993 April; 13(4): 2224-2234




This article has been cited by other articles:

  • Braconi, C., Bracci, R., Bearzi, I., Bianchi, F., Costagliola, A., Catalani, R., Mandolesi, A., Ranaldi, R., Galizia, E., Cascinu, S., Rossi, G., Giustini, L., Latini, L., Valeri, N., Cellerino, R. (2008). KIT and PDGFR{alpha} mutations in 104 patients with gastrointestinal stromal tumors (GISTs): a population-based study. Ann Oncol 19: 706-710 [Abstract] [Full Text]  
  • Xiang, Z., Kreisel, F., Cain, J., Colson, A., Tomasson, M. H. (2007). Neoplasia Driven by Mutant c-KIT Is Mediated by Intracellular, Not Plasma Membrane, Receptor Signaling. Mol. Cell. Biol. 27: 267-282 [Abstract] [Full Text]  
  • Gidwitz, S., Lyman, S., White, G. C. II (2000). Expression and Function of Calcium Binding Domain Chimeras of the Integrins alpha IIb and alpha 5. J. Biol. Chem. 275: 6680-6688 [Abstract] [Full Text]  
  • Tsujimura, T., Hashimoto, K., Kitayama, H., Ikeda, H., Sugahara, H., Matsumura, I., Kaisho, T., Terada, N., Kitamura, Y., Kanakura, Y. (1999). Activating Mutation in the Catalytic Domain of c-kit Elicits Hematopoietic Transformation by Receptor Self-Association Not at the Ligand-Induced Dimerization Site. Blood 93: 1319-1329 [Abstract] [Full Text]  
  • Lokker, N. A., O'Hare, J. P., Barsoumian, A., Tomlinson, J. E., Ramakrishnan, V., Fretto, L. J., Giese, N. A. (1997). Functional Importance of Platelet-derived Growth Factor (PDGF) Receptor Extracellular Immunoglobulin-like Domains. IDENTIFICATION OF PDGF BINDING SITE AND NEUTRALIZING MONOCLONAL ANTIBODIES. J. Biol. Chem. 272: 33037-33044 [Abstract] [Full Text]  
  • Ferrao, P., Gonda, T. J., Ashman, L. K. (1997). Expression of Constitutively Activated Human c-Kit in Myb Transformed Early Myeloid Cells Leads to Factor Independence, Histiocytic Differentiation, and Tumorigenicity. Blood 90: 4539-4552 [Abstract] [Full Text]  
  • Broudy, V. C. (1997). Stem Cell Factor and Hematopoiesis. Blood 90: 1345-1364 [Full Text]  
  • Barleon, B., Totzke, F., Herzog, C., Blanke, S., Kremmer, E., Siemeister, G., Marme, D., Martiny-Baron, G. (1997). Mapping of the Sites for Ligand Binding and Receptor Dimerization at the Extracellular Domain of the Vascular Endothelial Growth Factor Receptor FLT-1. J. Biol. Chem. 272: 10382-10388 [Abstract] [Full Text]  
  • Lemmon, M. A., Pinchasi, D., Zhou, M., Lax, I., Schlessinger, J. (1997). Kit Receptor Dimerization Is Driven by Bivalent Binding of Stem Cell Factor. J. Biol. Chem. 272: 6311-6317 [Abstract] [Full Text]  
  • Hsu, Y.-R., Wu, G.-M., Mendiaz, E. A., Syed, R., Wypych, J., Toso, R., Mann, M. B., Boone, T. C., Narhi, L. O., Lu, H. S., Langley, K. E. (1997). The Majority of Stem Cell Factor Exists as Monomer under Physiological Conditions. IMPLICATIONS FOR DIMERIZATION MEDIATING BIOLOGICAL ACTIVITY. J. Biol. Chem. 272: 6406-6415 [Abstract] [Full Text]  
  • Philo, J. S., Wen, J., Wypych, J., Schwartz, M. G., Mendiaz, E. A., Langley, K. E. (1996). Human Stem Cell Factor Dimer Forms a Complex with Two Molecules of the Extracellular Domain of Its Receptor, Kit. J. Biol. Chem. 271: 6895-6902 [Abstract] [Full Text]  
  • Koshimizu, U, Taga, T, Watanabe, M, Saito, M, Shirayoshi, Y, Kishimoto, T, Nakatsuji, N (1996). Functional requirement of gp130-mediated signaling for growth and survival of mouse primordial germ cells in vitro and derivation of embryonic germ (EG) cells. Development 122: 1235-1242 [Abstract]  
  • Lavagna, C., Marchetto, S., Birnbaum, D., Rosnet, O. (1995). Identification and Characterization of a Functional Murine FLT3 Isoform Produced by Exon Skipping. J. Biol. Chem. 270: 3165-3171 [Abstract] [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»