Submitted April 25, 2006
Accepted August 17, 2006
SHP-2 phosphatase is required for hematopoietic cell transformation by Bcr-Abl
Jing Chen, Wen-Mei Yu, Hanako Daino, Hal E. Broxmeyer, Brian J. Druker, and Cheng-Kui Qu*
Dept of Medicine, Division of Hematology/Oncology, Case Comprehensive Cancer Center, Cleveland, OH
Walther Oncology Center & Dept of Immunology & Microbiology, Indianapolis, Indiana, USA
Howard Hughes Medical Institute, Oregon Health & Science University Cancer Institute, Portland, OR
* Corresponding author; email: cxq6{at}case.edu.
SHP-2 phosphatase forms a stable protein complex with and is heavily tyrosine-phosphorylated by the oncogenic tyrosine kinase Bcr-Abl. However, the role of SHP-2 in Bcr-Abl-mediated leukemogenesis is unclear. In the present report, we provide evidence that SHP-2 is required for hematopoietic cell transformation by Bcr-Abl. In vitro biological effects of Bcr-Abl transduction were diminished in SHP-2
/ hematopoietic cells, and the leukemic potential of Bcr-Abl transduced SHP-2/ cells in recipient animals was compromised. Further analyses showed that Bcr-Abl protein (p210) was degraded and its oncogenic signaling greatly decreased in SHP-2/ cells. Treatment with proteasome inhibitors or reintroduction of SHP-2 restored p210 level in Bcr-Abl transduced SHP-2/ cells. Subsequent investigation revealed that SHP-2 interacted with heat shock protein 90, an important chaperone protein protecting p210 from proteasome-mediated degradation. The role of SHP-2 in the stability of p210 is independent of its catalytic activity. Blockade of SHP-2 expression in p210 expressing cells by antisense or small interfering RNA approaches decreased p210 level, causing cell death. Inhibition of SHP-2 enzymatic activity by overexpression of catalytically-inactive SHP-2 mutant did not destabilize p210, but enhanced serum starvation-induced apoptosis, suggesting that SHP-2 also plays an important role in downstream signaling of p210 kinase. These studies identified a novel function of SHP-2 and suggest that SHP-2 might be a useful target for controlling Bcr-Abl-positive leukemias.
