|
|
Blood, 15 January 2007, Vol. 109, No. 2, pp. 778-785.
Prepublished online as a Blood First Edition Paper on September 26, 2006; DOI 10.1182/blood-2006-04-019141.
 Previous Article | Next Article 
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.
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati What's this?
This article has been cited by other articles:
|
|
|
|
 
M. Brehme, O. Hantschel, J. Colinge, I. Kaupe, M. Planyavsky, T. Kocher, K. Mechtler, K. L. Bennett, and G. Superti-Furga
Charting the molecular network of the drug target Bcr-Abl
PNAS,
May 5, 2009;
106(18):
7414 - 7419.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Mitra, C. Beach, G.-S. Feng, and R. Plattner
SHP-2 is a novel target of Abl kinases during cell proliferation
J. Cell Sci.,
October 15, 2008;
121(20):
3335 - 3346.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
G.-M. Zou and A. Maitra
Small-molecule inhibitor of the AP endonuclease 1/REF-1 E3330 inhibits pancreatic cancer cell growth and migration
Mol. Cancer Ther.,
July 1, 2008;
7(7):
2012 - 2021.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. Voena, C. Conte, C. Ambrogio, E. Boeri Erba, F. Boccalatte, S. Mohammed, O. N. Jensen, G. Palestro, G. Inghirami, and R. Chiarle
The Tyrosine Phosphatase Shp2 Interacts with NPM-ALK and Regulates Anaplastic Lymphoma Cell Growth and Migration
Cancer Res.,
May 1, 2007;
67(9):
4278 - 4286.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
