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Molecular and Cellular Biology, October 2001, p. 6851-6858, Vol. 21, No. 20
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.20.6851-6858.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Hematopoietic Protein Tyrosine Phosphatase Suppresses Extracellular Stimulus-Regulated Kinase Activation

Marcela Gronda,1 Sara Arab,1 Barbara Iafrate,1 Haruhiko Suzuki,2 and Brent W. Zanke1,3,*

Departments of Medicine3 and Medical Biophysics,1 University of Toronto, Princess Margaret Hospital and Ontario Cancer Institute, Toronto, Ontario M5G 2M9, Canada, and Nagoya School of Medicine, Showa-ku, Nagoya 464, Japan2

Received 13 February 2001/Returned for modification 13 March 2001/Accepted 19 July 2001

The mitogen-activated protein kinases (MAPKs) are signaling molecules that become enzymatically activated through phosphorylation by diverse stimuli. Hematopoietic cytokines, growth factors, and stimulated lymphocyte antigen receptors may activate specific MAPKs by altering the balance of MAPK-activating protein kinases and the protein phosphatases that target their activation sites. Hematopoietic protein tyrosine phosphatase (HePTP) is a hematopoiesis-specific cytoplasmic protein tyrosine phosphatase whose expression is induced by mitogenic stimuli. To investigate the role of HePTP in hematopoietic development, we constructed mice deficient in this phosphatase using the technique of homologous recombination. Primary lymphocytes from HePTP-/- mice show enhanced activation of extracellular stimulus-regulated kinase (ERK) after both phorbol myristate acetate (PMA) and anti-CD3-mediated T-cell receptor (TCR) stimulation, suggesting a true physiological relationship between these two molecules. Activation of MEK, the physiological activator of ERK, by anti-CD3 or PMA is not affected by HePTP deletion. The distribution of hematopoietic lineages in bone marrow and peripheral blood samples and the in vitro proliferative capacity of bone marrow progenitors from HePTP deletion mice do not deviate from those of matched littermate controls. Similarly, lymphocyte activation and development are indistinguishable in HePTP-/- mice and controls. We conclude that HePTP is a physiological regulator of ERK on the basis of these studies and hypothesize that its deletion is well compensated for in the developing mouse through reduction of ERK targets or enhancement of physiologically opposed signaling pathways.

* Corresponding author. Present address: The Cross Cancer Institute, 51160 University Avenue, Edmonton, Alberta T6G 1Z2, Canada. Phone: (780) 432-8771. Fax: (780) 432-8411. E-mail: zanke{at}cancerboard.ab.ca.

Molecular and Cellular Biology, October 2001, p. 6851-6858, Vol. 21, No. 20
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.20.6851-6858.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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