Hematopoietic protein tyrosine phosphatase suppresses extracellular stimulus-regulated kinase activation

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-activ ating protein kinases and the protein phosphatases that target their activa tion sites. Hematopoietic protein tyrosine phosphatase (HePTP) is a hematop oiesis-specific cytoplasmic protein tyrosine phosphatase whose expression i s induced by mitogenic stimuli. To investigate the role of HePTP in hematop oietic 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-c ell receptor (TCR) stimulation, suggesting a true physiological relationshi p between these two molecules. Activation of MEK, the physiological activat or of ERK, by anti-CD3 or PMA is not affected by HePTP deletion. The distri bution of hematopoietic lineages in bone marrow and peripheral blood sample s and the in vitro proliferative capacity of bone marrow progenitors from H ePTP deletion juice do not deviate from those of matched littermate control s. Similarly, lymphocyte activation and development are indistinguishable i n HePTP-/- mice and controls. We conclude that HePTP is a physiological reg ulator of ERK on the basis of these studies and hypothesize that its deleti on is well compensated for in the developing mouse through reduction of ERK targets or enhancement of physiologically opposed signaling pathways.