Role of SHP2 phosphatase in KIT-induced transformation: identification of SHP2 as a druggable target in diseases involving oncogenic KIT.
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.
Department of Pediatrics, Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Raghuveer Singh
RS
Mali
Peilin
P
Ma
Li-Fan
LF
Zeng
Holly
H
Martin
Baskar
B
Ramdas
Yantao
Y
He
Emily
E
Sims
Sarah
S
Nabinger
Joydeep
J
Ghosh
Namit
N
Sharma
Veerendra
V
Munugalavadla
Anindya
A
Chatterjee
Shuo
S
Li
George
G
Sandusky
Andrew W
AW
Craig
Kevin D
KD
Bunting
Gen-Sheng
GS
Feng
Rebecca J
RJ
Chan
Zhong-Yin
ZY
Zhang
Reuben
R
Kapur
D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D016026:Bone Marrow Transplantation; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000473:pathology*; D058543:Class Ia Phosphatidylinositol 3-Kinase / Q000378:metabolism; D051380:GRB2 Adaptor Protein / Q000502:physiology*; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D047468:Immunoprecipitation; D019426:Integrases / Q000378:metabolism; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D009154:Mutation / Q000235:genetics*; D009196:Myeloproliferative Disorders / Q000209:etiology* / Q000401:mortality / Q000517:prevention & control*; D010766:Phosphorylation / Q000187:drug effects; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000037:antagonists & inhibitors / Q000502:physiology*; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D015996:Survival Rate; D014443:Tyrosine / Q000378:metabolism
D051380:GRB2 Adaptor Protein; C495949:Grb2 protein, mouse; D014443:Tyrosine; D058543:Class Ia Phosphatidylinositol 3-Kinase; D019009:Proto-Oncogene Proteins c-kit; C045073:Cre recombinase; D019426:Integrases; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11