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KIT-D816V oncogenic activity is controlled by the juxtamembrane docking site Y568-Y570

Oncogene volume 33, pages 872–881 (2014)Cite this article

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Abstract

Mutation of KIT receptor tyrosine kinase at residue D816 results in ligand-independent constitutive kinase activity. This mutation occurs in most patients with mastocytosis, a myeloproliferative neoplasm, and is detected at lower frequencies in acute myeloid leukemia and in germ cell tumors. Other KIT mutations occur in gastrointestinal stromal tumors (GIST) and mucosal melanoma. KIT is considered as a bona fide therapeutic target as c-kit mutations are driving oncogenes in these pathologies. However, several evidences suggest that KIT-D816V mutant is not as aggressive as other KIT mutants. Here, we show that an intracellular docking site in the juxtamembrane region of KIT maintains a negative regulation on KIT-D816V transforming potential. Sixteen signaling proteins were shown to interact with this motif. We further demonstrate that mutation of this site results in signaling modifications, altered gene expression profile and increased transforming activity of KIT-D816V mutant. This result was unexpected as mutations of the homologous sites on wild-type (WT) KIT, or on the related oncogenic FLT3-ITD receptor, impair their function. Our results support the hypothesis that, KIT-D816V mutation is a mild oncogenic event that is sufficient to confer partial transforming properties, but requires additional mutations to acquire its full transforming potential.

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Acknowledgements

We thank Cyndie Mosca, F Bardin and K Hanssens for technical assistance. AC is a recipient of PhD fellowships from Ministère de la Recherche-ENS, ARC and a financial support from the French Society of Hematology. We acknowledge postdoctoral fellowships from FRM and Institut Lilly to MLA, from INCa and OSEO to SL and from FRM to MV. This project was supported by grants from la Ligue Contre le Cancer and INCa.

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Author notes

  1. M-L Arcangeli and S Lopez: These authors contributed equally to this work.

Authors and Affiliations

  1. INSERM, U1068, Centre de Recherche en Cancérologie de Marseille, Marseille, France

    A Chaix, M-L Arcangeli, S Lopez, E Voisset, Y Yang, M Vita, S Letard, S Audebert, P Finetti, D Birnbaum, F Bertucci, M Aurrand-Lions, P Dubreuil & P De Sepulveda

  2. Institut Paoli-Calmettes, Marseille, France

    A Chaix, M-L Arcangeli, S Lopez, E Voisset, Y Yang, M Vita, S Letard, S Audebert, P Finetti, D Birnbaum, F Bertucci, M Aurrand-Lions, P Dubreuil & P De Sepulveda

  3. Aix-Marseille University, Marseille, France

    A Chaix, M-L Arcangeli, S Lopez, E Voisset, Y Yang, M Vita, S Letard, S Audebert, P Finetti, D Birnbaum, F Bertucci, M Aurrand-Lions, P Dubreuil & P De Sepulveda

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  1. A Chaix
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Correspondence to P De Sepulveda.

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Chaix, A., Arcangeli, ML., Lopez, S. et al. KIT-D816V oncogenic activity is controlled by the juxtamembrane docking site Y568-Y570. Oncogene 33, 872–881 (2014). https://doi.org/10.1038/onc.2013.12

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