Hematopoietic Protein Tyrosine Phosphatase Suppresses Extracellular Stimulus-Regulated Kinase Activation

Abstract

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.

ACKNOWLEDGMENTS

This work was supported by grants from the National Cancer Institute of Canada to B. Zanke. We thank T. W. Mak for assistance with homologous recombination experiments, Joseph Penninger for his guidance in experiments evaluating T-cell proliferation and TCR-induced ERK activation, Norman Iscove and Deborah Hyam for assistance with experiments involving the hybridization of lineage blots and culture of mouse bone marrow, Kaliannan Raju for assistance with T-helper 1 and 2 differentiation experiments, and Christine Quarrinton and her team at the OCI Animal Resource Centre for assistance with animal care.