title: Oncogenic signaling by Kit tyrosine kinase occurs selectively on the Golgi apparatus in gastrointestinal stromal tumors.
abstract: Gastrointestinal stromal tumors (GISTs) are caused by gain-of-function mutations in the Kit receptor tyrosine kinase. Most primary GIST patients respond to the Kit inhibitor imatinib, but this drug often becomes ineffective because of secondary mutations in the Kit kinase domain. The characteristic intracellular accumulation of imatinib-sensitive and -resistant Kit protein is well documented, but its relationship to oncogenic signaling remains unknown. Here, we show that in cancer tissue from primary GIST patients as well as in cell lines, mutant Kit accumulates on the Golgi apparatus, whereas normal Kit localizes to the plasma membrane (PM). In imatinib-resistant GIST with a secondary Kit mutation, Kit localizes predominantly on the Golgi apparatus. Both imatinib-sensitive and imatinib-resistant Kit (Kit(mut)) become fully auto-phosphorylated only on the Golgi and only if in a complex-glycosylated form. Kit(mut) accumulates on the Golgi during the early secretory pathway, but not after endocytosis. The aberrant kinase activity of Kit(mut) prevents its export from the Golgi to the PM. Furthermore, Kit(mut) on the Golgi signals and activates the phosphatidylinositol 3-kinase-Akt (PI3K-Akt) pathway, signal transducer and activator of transcription 5 (STAT5), and the Mek-Erk pathway. Blocking the biosynthetic transport of Kit(mut) to the Golgi from the endoplasmic reticulum inhibits oncogenic signaling. PM localization of Kit(mut) is not required for its signaling. Activation of Src-family tyrosine kinases on the Golgi is essential for oncogenic Kit signaling. These results suggest that the Golgi apparatus serves as a platform for oncogenic Kit signaling. Our study demonstrates that Kit(mut)'s pathogenicity is related to its mis-localization, and may offer a new strategy for treating imatinib-resistant GISTs.
authors.affiliation: Division of Immunobiology, Research Institute for Biomedical Sciences, Tokyo University of Science, Noda, Chiba, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Obata
authors.affiliation: Division of Immunobiology, Research Institute for Biomedical Sciences, Tokyo University of Science, Noda, Chiba, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Horikawa
authors.affiliation: Department of Surgery, Osaka University, Graduate School of Medicine, Suita, Osaka, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Takahashi
authors.affiliation: Division of Immunobiology, Research Institute for Biomedical Sciences, Tokyo University of Science, Noda, Chiba, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Akieda
authors.affiliation: Department of Diagnostic Pathology, Osaka Police Hospital, Osaka, Osaka, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Tsujimoto
authors.affiliation: Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: J A
authors.initials: JA
authors.lastname: Fletcher
authors.affiliation: Division of Clinical Research, Research Institute for Biomedical Sciences, Tokyo University of Science, Noda, Chiba, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Esumi
authors.affiliation: National Cancer Center Hospital, Chuo-ku, Tokyo, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Nishida
authors.affiliation: Division of Immunobiology, Research Institute for Biomedical Sciences, Tokyo University of Science, Noda, Chiba, Japan.
authors.forename: R
authors.initials: R
authors.lastname: Abe
mesh_terms: D000818:Animals; D063646:Carcinogenesis; D045744:Cell Line, Tumor; D005770:Gastrointestinal Neoplasms / Q000201:enzymology / Q000235:genetics*; D046152:Gastrointestinal Stromal Tumors / Q000201:enzymology / Q000235:genetics*; D006056:Golgi Apparatus / Q000201:enzymology*; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D014162:Transfection
chemical_list: D019009:Proto-Oncogene Proteins c-kit