Gain-of-Function Mutations of c-
            <i>kit</i>
            in Human Gastrointestinal Stromal Tumors

Hirota, Seiichi; Isozaki, Koji; Moriyama, Y; Hashimoto, Koji; Nishida, Toshirou; Ishiguro, Shingo; Kawano, Kiyoshi; Hanada, Masato; Kurata, Akihiko; Takeda, Masatoshi; Tunio, Ghulam Muhammad; Matsuzawa, Yūji; Kanakura, Yuzuru; Shinomura, Yasuhisa; Kitamura, Yukihiko

doi:10.1126/science.279.5350.577

Cited by 4,087 publications

(2,997 citation statements)

References 22 publications

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“…[12][13][14][15][16] Gain-offunction mutations of the c-kit gene lead to stem cell factor-independent activation of intracytoplasmic signal transduction and finally tumor growth and differentiation. c-kit mutations have been found in mast cell tumors 17 and gastrointestinal stromal tumors (GISTs), 18 which are classified on the basis of About two-thirds of GISTs coexpress CD34 19,20 and/or bcl-2. 9,10,21-23 Expression of c-kit, CD34 and bcl-2 in the stromal elements suggests a GIST, which may also occur outside the gut.…”

Section: Resultsmentioning

confidence: 99%

Cellular hamartoma resembling gastrointestinal stromal tumor: a solid tumor of the pancreas expressing c-kit (CD117)

et al. 2005

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Solid tumors of the pancreas are usually neoplastic. We report on two adult patients, each with a solid tumor of the pancreas that presented with an unusual histology and seemed to follow a benign course. The tumors, one located in the body and one in the tail, were well demarcated and composed of irregularly arranged but welldifferentiated acini and small intralobular and interlobular ducts embedded in predominantly hypocellular fibrotic tissue that contained fascicles of cytologically bland spindle cells. Islets were lacking, but immunohistochemical staining for chromogranin A and insulin revealed individual scattered insulin-producing cells distributed between acinar and ductal cells. The spindle cell component tissue showed coexpression of CD34, c-kit (CD117) and bcl-2. The follow-up (2 and 4 years) of the patients was uneventful. We propose to designate the tumors as 'cellular hamartoma resembling gastrointestinal stromal tumor.' Modern Pathology ( Keywords: pancreatic tumor; hamartoma; c-kit; CD34; bcl-2; differential diagnosis Well-demarcated tumor-like lesions in the pancreas are uncommon. They have been described under the term pseudotumor 1 or inflammatory pseudotumor. 2 Recently, we described a tumorous lesion that we termed pancreatic solid and cystic hamartoma. 3 Here we report on two further solid pancreatic tumors that have features in common with both hamartomas and gastrointestinal stromal tumors. Patients, materials and methodsThe cases were collected from the consultation files of the Department of Pathology of the University of Kiel, to which they had been submitted by the Department of Pathology in Dinslaken, Germany (case 1), and the Department of Pathology of the University of Coimbra, Portugal (case 2).In the first case, a 51-year-old man without clinical symptoms had a routine check-up, during which a mass, 3 cm in diameter, was detected by ultrasonography in the tail of the pancreas next to the splenic artery. This finding was confirmed by endosonography and CT. Laboratory tests were normal. As a result of the unclear nature of the tumor, abdominal surgery was performed with resection of the tumor.In the second case, a 54-year-old woman with slight abdominal discomfort was examined by ultrasonography, which revealed a well-demarcated tumor, 2 cm in diameter, in the body of the pancreas. A left-sided pancreatic resection was performed to remove the tumor. Both patients had an uncomplicated postoperative course and so far (2 and 4 years, respectively) have relapse-free follow-up.Representative 4 mm sections of formalin-fixed, paraffin-embedded tissue from both specimens were stained with hematoxylin and eosin (H&E) and periodic acid-Schiff. Immunohistochemical staining was performed using the standard avidinbiotin method against following antibodies: cytokeratin 8 (CAM 5

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Section: Resultsmentioning

confidence: 99%

Cellular hamartoma resembling gastrointestinal stromal tumor: a solid tumor of the pancreas expressing c-kit (CD117)

et al. 2005

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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%

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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“…The juxtamembrane domains of receptor tyrosine kinases have important but poorlyunderstood regulatory functions (Myles et al, 1994;Herbst et al, 1995;Hirota et al, 1998). Studies are underway aiming at the identi®cation of the signaling components that link the juxtamembrane region of the PDGF receptor to STAT activation.…”

Section: Discussionmentioning

confidence: 99%

STAT activation by the PDGF receptor requires juxtamembrane phosphorylation sites but not Src tyrosine kinase activation

1999

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Activation of the platelet-derived growth factor (PDGF) receptor tyrosine kinase induces tyrosine phosphorylation of Signal Transducer and Activator of Transcription (STAT) proteins. Since the PDGF receptor also activates the Src tyrosine kinase, it is possible that Src mediates tyrosine phosphorylation of STATs in PDGFtreated cells. Consistent with a role for Src in STAT activation, we found that a PDGF receptor juxtamembrane tyrosine residue required for Src activation is necessary and su cient for activation of STATs 1 and 3. To test the Src requirement further, we made other mutations in the PDGF receptor juxtamembrane region that increased or decreased Src binding. In epithelial and ®broblast cells, PDGF activated STAT1, 3 and 6 in the absence of detectable binding and activation of Src. In addition, PDGF induced c-myc RNA expression and DNA synthesis even though Src was not detectably activated. The activation of MAP kinase and the induction of c-fos gene expression both correlated with STAT but not Src activation by the receptor. We conclude that juxtamembrane tyrosine phosphorylation is necessary for both Src tyrosine kinase and STAT activation by the bPDGF receptor, but that both processes are regulated independently by this region.

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Gain-of-Function Mutations of c- kit in Human Gastrointestinal Stromal Tumors

Cited by 4,087 publications

References 22 publications

Cellular hamartoma resembling gastrointestinal stromal tumor: a solid tumor of the pancreas expressing c-kit (CD117)

Cellular hamartoma resembling gastrointestinal stromal tumor: a solid tumor of the pancreas expressing c-kit (CD117)

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

STAT activation by the PDGF receptor requires juxtamembrane phosphorylation sites but not Src tyrosine kinase activation

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