Role of SHP2 phosphatase in KIT-induced transformation: identification of SHP2 as a druggable target in diseases involving oncogenic KIT-Reference-Cited by-全球学者库

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

Published:2012-09-27 Issue:13 Volume:120 Page:2669-2678
ISSN:0006-4971
Container-title:Blood
language:en
Short-container-title:

Author:

Mali Raghuveer Singh¹,Ma Peilin¹,Zeng Li-Fan²,Martin Holly¹,Ramdas Baskar¹,He Yantao²,Sims Emily¹,Nabinger Sarah¹,Ghosh Joydeep¹,Sharma Namit³,Munugalavadla Veerendra⁴,Chatterjee Anindya¹,Li Shuo¹,Sandusky George⁵,Craig Andrew W.³,Bunting Kevin D.⁶,Feng Gen-Sheng⁷,Chan Rebecca J.¹,Zhang Zhong-Yin²,Kapur Reuben¹²

Affiliation:

1. Department of Pediatrics, Herman B. Wells Center for Pediatric Research and

2. Department of Biochemistry & Molecular Biology, Indiana University School of Medicine, Indianapolis, IN;

3. Department of Biochemistry, Queen's University, Kingston, ON;

4. Cancer Immunotherapy & Hematology, Genentech, South San Francisco, CA;

5. Department of Pathology, Indiana University School of Medicine, Indianapolis, IN;

6. Division of Hematology-Oncology, Emory University School of Medicine, Atlanta, GA; and

7. Department of Pathology, University of California, San Diego, La Jolla, CA

Abstract

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.

Publisher

American Society of Hematology

Subject

Cell Biology,Hematology,Immunology,Biochemistry

Link

http://ashpublications.org/blood/article-pdf/120/13/2669/1358389/zh803912002669.pdf

Reference42 articles.

1. Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors.;Hirota;Science,1998

2. Classes of c-KIT activating mutations: proposed mechanisms of action and implications for disease classification and therapy.;Longley;Leuk Res,2001

3. C-kit mutations in core binding factor leukemias.;Beghini;Blood,2000

4. Identification of a point mutation in the catalytic domain of the protooncogene c-kit in peripheral blood mononuclear cells of patients who have mastocytosis with an associated hematologic disorder.;Nagata;Proc Natl Acad Sci U S A,1995

5. Constitutively activating mutations of c-kit receptor tyrosine kinase confer factor-independent growth and tumorigenicity of factor-dependent hematopoietic cell lines.;Kitayama;Blood,1995

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