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.

Furitsu, Takuma; Tsujimura, Tohru; Tono, Tetsuzo; Ikeda, Hirokazu; Kitayama, Hitoshi; Koshimizu, Uichi; Sugahara, Hiroyuki; Butterfield, Joseph H.; Ashman, Leonie K.; Kanayama, Yoshio

doi:10.1172/jci116761

Cited by 761 publications

(616 citation statements)

References 54 publications

(38 reference statements)

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“…Numerous naturally occurring activating mutations found in Kit/SCFR reside in the juxtamembrane region, either as point mutations or deletions (Furitsu et al, 1993;Hirota et al, 1998). Furthermore, the viral form of Kit/SCFR, v-kit, contains deletions in its juxtamembrane region that accounts for its tumorigenic potential (Herbst et al, 1995).…”

Section: Discussionmentioning

confidence: 99%

“…Several signal transduction molecules have been found to be phosphorylated by and in some cases bind to the activated Kit/SCFR, including PI3'-kinase, Vav, Grb2 and Shc (Alai et al, 1992;Cutler et al, 1993;Lev et al, 1991;Tauchi et al, 1994). Several activating mutations of Kit/SCFR have been found in mast cell leukemias and gastrointestinal stroma tumors (Furitsu et al, 1993;Hirota et al, 1998). Interestingly, many of these mutations are either point mutations or deletion mutations in the juxtamembrane region of the Kit/SCFR.…”

Section: Introductionmentioning

confidence: 99%

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Phosphorylation of Shc by Src family kinases is necessary for stem cell factor receptor/c-kit mediated activation of the Ras/MAP kinase pathway and c-fos induction

et al. 1999

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In this report we show that Tyr568 and Tyr570 are phosphorylated in vivo in the Kit/stem cell factor receptor (Kit/SCFR) following ligand-stimulation. By mutation of Tyr568 and Tyr570 to phenylalanine residues and expression of the mutated receptors in porcine aortic endothelial (PAE) cells, we could demonstrate a loss of activation of members of the Src family of tyrosine kinases when Tyr568 was mutated, while mutation of Tyr570 only led to a minor decrease in activation of Src family members. Mutation of both tyrosine residues led to a complete loss of Src family kinase activation. Phosphorylation of the adapter protein Shc by growth factor receptors provides association sites for Grb2-Sos, thereby activating the Ras/MAP kinase pathway. A much lowered degree of Shc phosphorylation, Ras and Erk2 activation and c-fos induction was seen in the Y568F mutant, while in the Y570F mutant these responses were less a ected. In contrast, the mitogenic response was only slightly reduced. In a mutant receptor with both Tyr568 and Tyr570 mutated to phenylalanine residues, no phosphorylation of Shc and no activation of Ras and Erk2 was seen in response to stem cell factor stimulation, very weak induction of c-fos was seen and the mitogenic response was severely depressed. These data show that Ras/MAP kinase activation and c-fos induction by Kit/SCFR are mediated by members of the Src family kinases. However, the mitogenic response is only to a minor extent dependent on Src kinase activity.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Phosphorylation of Shc by Src family kinases is necessary for stem cell factor receptor/c-kit mediated activation of the Ras/MAP kinase pathway and c-fos induction

et al. 1999

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“…37,38 The human mast cell leukemia cell line HMC-1.2, which is known to display the KIT mutation D816V, served as a positive control. 21 HMC-1 cells were kindly provided by Dr Butterfield of the Mayo Clinic, Rochester, MN, USA.…”

Section: Analysis Of Kit Codon 816 Mutationsmentioning

confidence: 99%

“…5,8,[15][16][17][18][19][20] This mutation is associated with autonomous activation of the KIT receptor and is therefore considered to contribute to abnormal growth and survival of neoplastic mast cells in systemic mastocytosis. 21 As KIT D816V is detectable not only in aggressive systemic mastocytosis and mast cell leukemia but also in indolent systemic mastocytosis, 15,19,20 it is thought that additional pro-oncogenic pathways and markers trigger and are indicative of the aggressive disease variants, that is, aggressive systemic mastocytosis and mast cell leukemia. Unfortunately, such additional molecular markers and pathways have not yet been identified.…”

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confidence: 99%

Aberrant expression of CD30 in neoplastic mast cells in high-grade mastocytosis

Cerny-Reiterer²,

et al. 2011

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“…Examples of activating mutations directly a ecting the structure of the TK domain are those found in the tyrosine kinases Kit and Ret. The Kit mutation, which causes human mast cell leukaemia (Furitsu et al, 1993;Tsujimura et al, 1994) and human mastocytosis (Longley et al, 1996), consists of the substitution of a conserved aspartic acid residue located in subdomain VII of the kinase with a neutral residue (Hanks et al, 1988). In the case of the Ret receptor, a genetic alteration ®rst identi®ed in patients with the inherited cancer syndrome Multiple Endocrine Neoplasia type 2B (MEN2B), converts a methionine residue in subdomain VIII of the kinase into threonine (Carlson et al, 1994;Hofstra et al, 1994).…”

Section: Introductionmentioning

confidence: 99%

Point mutations in the tyrosine kinase domain release the oncogenic and metastatic potential of the ron receptor

Santoro¹,

Penengo

Minetto

et al. 1998

Oncogene

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Ron (the receptor for Macrophage Stimulating Protein) has never been implicated before in human malignancies or in cell transformation. In this report we show that Ron can acquire oncogenic potential by means of two amino acid substitutions ± D1232V and M1254T ± a ecting highly conserved residues in the tyrosine kinase domain. The same mutations in Kit and Ret have been found associated with two human malignancies, mastocytosis and Multiple Endocrine Neoplasia type 2B (MEN2B), respectively. Both mutations caused Ronmediated transformation of 3T3 ®broblasts and tumour formation in nude mice. Moreover, cells transformed by the oncogenic Ron mutants displayed high metastatic potential. The Ron mutant receptors were constitutively active and the catalytic e ciency of the mutated kinase was higher than that of wild-type Ron. Oncogenic Ron mutants enhanced activation of the Ras/MAPK cascade with respect to wild type Ron, without a ecting the JNK/SAPK pathway. Expression of Ron mutants in 3T3 ®broblasts led to di erent patterns of tyrosine-phosphorylated proteins. These data show that point mutations altering catalytic properties and possibly substrate speci®city of the Ron kinase may force cells toward tumorigenesis and metastasis.

show abstract

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.

Cited by 761 publications

References 54 publications

Phosphorylation of Shc by Src family kinases is necessary for stem cell factor receptor/c-kit mediated activation of the Ras/MAP kinase pathway and c-fos induction

Phosphorylation of Shc by Src family kinases is necessary for stem cell factor receptor/c-kit mediated activation of the Ras/MAP kinase pathway and c-fos induction

Aberrant expression of CD30 in neoplastic mast cells in high-grade mastocytosis

Point mutations in the tyrosine kinase domain release the oncogenic and metastatic potential of the ron receptor

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