title: Oncogenic Kit signals on endolysosomes and endoplasmic reticulum are essential for neoplastic mast cell proliferation.
abstract: Kit is a receptor-type tyrosine kinase found on the plasma membrane. It can transform mast cells through activating mutations. Here, we show that a mutant Kit from neoplastic mast cells from mice, Kit(D814Y), is permanently active and allows cells to proliferate autonomously. It does so by activating two signalling pathways from different intracellular compartments. Mutant Kit from the cell surface accumulates on endolysosomes through clathrin-mediated endocytosis, which requires Kit's kinase activity. Kit(D814Y) is constitutively associated with phosphatidylinositol 3-kinase, but the complex activates Akt only on the cytoplasmic surface of endolysosomes. It resists destruction because it is under-ubiquitinated. Kit(D814Y) also appears in the endoplasmic reticulum soon after biosynthesis, and there, can activate STAT5 aberrantly. These mechanisms of oncogenic signalling are also seen in rat and human mast cell leukemia cells. Thus, oncogenic Kit signalling occurs from different intracellular compartments, and the mutation acts by altering Kit trafficking as well as activation.
authors.affiliation: Division of Immunobiology, Research Institute for Biomedical Sciences, Tokyo University of Science, Noda, Chiba 278-0022, Japan.
authors.forename: Yuuki
authors.initials: Y
authors.lastname: Obata
authors.affiliation: Division of Immunobiology, Research Institute for Biomedical Sciences, Tokyo University of Science, Noda, Chiba 278-0022, Japan.
authors.forename: Shota
authors.initials: S
authors.lastname: Toyoshima
authors.affiliation: Division of Immunobiology, Research Institute for Biomedical Sciences, Tokyo University of Science, Noda, Chiba 278-0022, Japan.
authors.forename: Ei
authors.initials: E
authors.lastname: Wakamatsu
authors.affiliation: Division of Immunobiology, Research Institute for Biomedical Sciences, Tokyo University of Science, Noda, Chiba 278-0022, Japan.
authors.forename: Shunichi
authors.initials: S
authors.lastname: Suzuki
authors.affiliation: Division of Immunobiology, Research Institute for Biomedical Sciences, Tokyo University of Science, Noda, Chiba 278-0022, Japan.
authors.forename: Shuhei
authors.initials: S
authors.lastname: Ogawa
authors.affiliation: 1] Division of Clinical Research, Research Institute for Biomedical Sciences, Tokyo University of Science, Noda, Chiba 278-0022, Japan [2] National Cancer Center Hospital East, Kashiwa, Chiba 277-8577, Japan.
authors.forename: Hiroyasu
authors.initials: H
authors.lastname: Esumi
authors.affiliation: Division of Immunobiology, Research Institute for Biomedical Sciences, Tokyo University of Science, Noda, Chiba 278-0022, Japan.
authors.forename: Ryo
authors.initials: R
authors.lastname: Abe