Role of SHP2 phosphatase in KIT-induced transformation: Identification of SHP2 as a druggable target in diseases involving oncogenic KIT

Raghuveer Singh Mali, Peilin Ma, Li Fan Zeng, Holly Martin, Baskar Ramdas, Yantao He, Emily Sims, Sarah Nabinger, Joydeep Ghosh, Namit Sharma, Veerendra Munugalavadla, Anindya Chatterjee, Shuo Li, George Sandusky, Andrew W. Craig, Kevin D. Bunting, Gen Sheng Feng, Rebecca J. Chan, Zhong Yin Zhang, Reuben Kapur

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Abstract

Intracellular mechanism(s) that contribute to promiscuous signaling via oncogenic KIT in systemic mastocytosis and acute myelogenous leukemia are poorly understood.We show that SHP2 phosphatase is essential for oncogenic KIT-induced growth and survival in vitro and myeloproliferative disease (MPD) in vivo. Genetic disruption of SHP2 or treatment of oncogene-bearing cells with a novel SHP2 inhibitor alone or in combination with the PI3K inhibitor corrects MPD by disrupting a protein complex involving p85α, SHP2, and Gab2. Importantly, a single tyrosine at position 719 in oncogenic KIT is sufficient to develop MPD by recruiting p85α, SHP2, and Gab2 complex to oncogenic KIT. Our results demonstrate that SHP2 phosphatase is a druggable target that cooperates with lipid kinases in inducing MPD.

Original languageEnglish (US)
Pages (from-to)2669-2678
Number of pages10
JournalBlood
Volume120
Issue number13
DOIs
StatePublished - Sep 27 2012

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ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

Mali, R. S., Ma, P., Zeng, L. F., Martin, H., Ramdas, B., He, Y., Sims, E., Nabinger, S., Ghosh, J., Sharma, N., Munugalavadla, V., Chatterjee, A., Li, S., Sandusky, G., Craig, A. W., Bunting, K. D., Feng, G. S., Chan, R. J., Zhang, Z. Y., & Kapur, R. (2012). Role of SHP2 phosphatase in KIT-induced transformation: Identification of SHP2 as a druggable target in diseases involving oncogenic KIT. Blood, 120(13), 2669-2678. https://doi.org/10.1182/blood-2011-08-375873