Oncogenic Kit signals on endolysosomes and endoplasmic reticulum are essential for neoplastic mast cell proliferation

Yuuki Obata, Shota Toyoshima, Ei Wakamatsu, Shunichi Suzuki, Shuhei Ogawa, Hiroyasu Esumi and Ryo Abe ()
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Yuuki Obata: Research Institute for Biomedical Sciences, Tokyo University of Science
Shota Toyoshima: Research Institute for Biomedical Sciences, Tokyo University of Science
Ei Wakamatsu: Research Institute for Biomedical Sciences, Tokyo University of Science
Shunichi Suzuki: Research Institute for Biomedical Sciences, Tokyo University of Science
Shuhei Ogawa: Research Institute for Biomedical Sciences, Tokyo University of Science
Hiroyasu Esumi: Research Institute for Biomedical Sciences, Tokyo University of Science
Ryo Abe: Research Institute for Biomedical Sciences, Tokyo University of Science

Nature Communications, 2014, vol. 5, issue 1, 1-17

Abstract: 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.

Date: 2014
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DOI: 10.1038/ncomms6715

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