A loss-of-function mutation of c-kit results in depletion of mast cells and interstitial cells of Cajal, while its gain-of-function mutation results in their oncogenesis.

Loss-of-function mutations of the c-kit receptor tyrosine kinase (KIT) result in depletion of mast cells and interstitial cells of Cajal (ICCs). In contrast, gain-of-function mutations of KIT induce neoplasms of mast cells and ICCs. In humans, the sites of mutations are different between mast cell neoplasms and those of ICCs. The former were found in the juxtamembrane domain between the transmembrane and tyrosine kinase domains, and the latter in the tyrosine kinase domain. Moreover, the mechanism of constitutive activation is different. Point mutations and/or deletions in the juxtamembrane domain induced the KIT dimerization, and the dimerized KIT was activated. A point mutation at the particular aspartic acid in the tyrosine kinase domain induced spontaneous activation without forming dimers. Mutations of the c-kit gene are a good model for understanding the relationship between mutations and diseases in both humans and mice.

[1]  David A. Williams,et al.  Stem cell factor is encoded at the SI locus of the mouse and is the ligand for the c-kit tyrosine kinase receptor , 1990, Cell.

[2]  Y. Matsuzawa,et al.  Constitutive activation of c-kit in FMA3 murine mastocytoma cells caused by deletion of seven amino acids at the juxtamembrane domain. , 1996, Blood.

[3]  Y. Kitamura,et al.  Coincidental development of forestomach papilloma and prepyloric ulcer in nontreated mutant mice of W/Wv and SI/SId genotypes. , 1980, Cancer research.

[4]  E. Russell.  Hereditary anemias of the mouse: a review for geneticists. , 1979, Advances in genetics.

[5]  Y. Kitamura,et al.  Anemia and mast cell depletion in mutant rats that are homozygous at "white spotting (Ws)" locus. , 1991, Blood.

[6]  P. Leder,et al.  The kit ligand: A cell surface molecule altered in steel mutant fibroblasts , 1990, Cell.

[7]  Yukihiko Kitamura,et al.  Decrease of mast cells in w/wv mice and their increase by bone marrow transplantation. , 1978 .

[8]  A. Burns,et al.  Impaired development of interstitial cells and intestinal electrical rhythmicity in steel mutants. , 1995, The American journal of physiology.

[9]  K. Nocka,et al.  Molecular bases of dominant negative and loss of function mutations at the murine c‐kit/white spotting locus: W37, Wv, W41 and W. , 1990, The EMBO journal.

[10]  John Malysz,et al.  W/kit gene required for interstitial cells of Cajal and for intestinal pacemaker activity , 1995, Nature.

[11]  Y. Suzuki,et al.  Identification of a point mutation in the catalytic domain of the protooncogene c-kit in peripheral blood mononuclear cells of patients who have mastocytosis with an associated hematologic disorder. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[12]  John E. Murphy,et al.  A new acute transforming feline retrovirus and relationship of its oncogene v-kit with the protein kinase gene family , 1986, Nature.

[13]  D. Housman,et al.  The dominant-white spotting (W) locus of the mouse encodes the c-kit proto-oncogene , 1988, Cell.

[14]  Y. Matsuzawa,et al.  Substitution of an aspartic acid results in constitutive activation of c-kit receptor tyrosine kinase in a rat tumor mast cell line RBL-2H3. , 1995, International archives of allergy and immunology.

[15]  M. Tatsuta,et al.  Bile reflux: a possible cause of stomach ulcer in nontreated mutant mice of W/WV genotype. , 1982, Gastroenterology.

[16]  S. Hirota,et al.  Cause of familial and multiple gastrointestinal autonomic nerve tumors with hyperplasia of interstitial cells of Cajal is germline mutation of the c-kit gene. , 2000, The American journal of surgical pathology.

[17]  L. Ashman,et al.  Identification of mutations in the coding sequence of the proto-oncogene c-kit in a human mast cell leukemia cell line causing ligand-independent activation of c-kit product. , 1993, The Journal of clinical investigation.

[18]  F. Ruddle,et al.  Primary structure of c‐kit: relationship with the CSF‐1/PDGF receptor kinase family–oncogenic activation of v‐kit involves deletion of extracellular domain and C terminus. , 1988, The EMBO journal.

[19]  H. Kitayama,et al.  Transforming and differentiation-inducing potential of constitutively activated c-kit mutant genes in the IC-2 murine interleukin-3-dependent mast cell line. , 1996, The American journal of pathology.

[20]  Y. Kitamura,et al.  Decreased production of mast cells in S1/S1d anemic mice. , 1979, Blood.

[21]  S. Hirota,et al.  Familial gastrointestinal stromal tumours with germline mutation of the KIT gene , 1998, Nature Genetics.

[22]  Laura H. Tang,et al.  Somatic c-KIT activating mutation in urticaria pigmentosa and aggressive mastocytosis: establishment of clonality in a human mast cell neoplasm , 1996, Nature Genetics.

[23]  Joseph Schlessinger,et al.  Signal transduction by receptors with tyrosine kinase activity , 1990, Cell.

[24]  C. March,et al.  Identification of a ligand for the c-kit proto-oncogene , 1990, Cell.

[25]  Y. Kitamura,et al.  Clonal nature of mast-cell clusters formed in W/Wv mice after bone marrow transplantation , 1979, Nature.

[26]  S. Hirota,et al.  Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors. , 1998, Science.

[27]  S. Nishikawa,et al.  Requirement of c-kit for development of intestinal pacemaker system. , 1992, Development.

[28]  E. Morii,et al.  Characterization of Ws mutant allele of rats: a 12-base deletion in tyrosine kinase domain of c-kit gene. , 1991, Blood.

[29]  S. Hirota,et al.  Disturbed intestinal movement, bile reflux to the stomach, and deficiency of c-kit-expressing cells in Ws/Ws mutant rats. , 1995, Gastroenterology.

[30]  S. Hirota,et al.  Effect of c-kit mutation on prognosis of gastrointestinal stromal tumors. , 1999, Cancer research.

[31]  C. Prosser,et al.  Boundary cells between longitudinal and circular layers: essential for electrical slow waves in cat intestine. , 1986, The American journal of physiology.

[32]  A. Ullrich,et al.  Human proto‐oncogene c‐kit: a new cell surface receptor tyrosine kinase for an unidentified ligand. , 1987, The EMBO journal.

[33]  V. Chapman,et al.  The proto-oncogene c-kit encoding a transmembrane tyrosine kinase receptor maps to the mouse W locus , 1988, Nature.

[34]  H. Kitayama,et al.  Constitutively activating mutations of c-kit receptor tyrosine kinase confer factor-independent growth and tumorigenicity of factor-dependent hematopoietic cell lines. , 1995, Blood.

[35]  S. Galli,et al.  Spontaneous canine mast cell tumors express tandem duplications in the proto-oncogene c-kit. , 1999, Experimental hematology.

[36]  Y. Matsuzawa,et al.  Ligand-independent activation of c-kit receptor tyrosine kinase in a murine mastocytoma cell line P-815 generated by a point mutation , 1994 .