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Hematopoietic protein tyrosine phosphatase suppresses extracellular stimulus-regulated kinase activation
1Department of Medical Biophysics, University of Toronto, Princess Margaret Hospital and Ontario Cancer Institute, Toronto, Ontario M5G 2M9, Canada.
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.
Insights
Hematopoietic protein tyrosine phosphatase (HePTP) regulates extracellular signal-regulated kinase (ERK) activation in lymphocytes. Mice lacking HePTP show enhanced ERK activation but normal hematopoietic development and lymphocyte function.
Area of Science:
- Cellular signaling pathways
- Immunology
- Hematopoiesis
Background:
- Mitogen-activated protein kinases (MAPKs) are crucial signaling molecules activated by various stimuli.
- Hematopoietic protein tyrosine phosphatase (HePTP) is a phosphatase induced by mitogenic signals in hematopoietic cells.
- The precise role of HePTP in hematopoietic development and lymphocyte signaling remains to be fully elucidated.
Purpose of the Study:
- To investigate the physiological role of HePTP in hematopoietic development and lymphocyte activation.
- To determine the relationship between HePTP and extracellular signal-regulated kinase (ERK) signaling.
Main Methods:
- Generation of HePTP-deficient mice (HePTP-/-) using homologous recombination.
- Analysis of primary lymphocyte activation (ERK phosphorylation) following stimulation with PMA and anti-TCR.
- Assessment of hematopoietic lineage distribution, progenitor proliferation, and lymphocyte development in HePTP-/- mice.
Main Results:
- HePTP-/- lymphocytes exhibited enhanced ERK activation upon PMA and anti-TCR stimulation.
- MEK activation, the upstream activator of ERK, was not affected by HePTP deletion.
- HePTP deficiency did not alter hematopoietic lineage distribution, progenitor proliferation, or overall lymphocyte development and activation.
Conclusions:
- HePTP functions as a physiological regulator of ERK activation in lymphocytes.
- The absence of HePTP is compensated in mice, potentially through modulation of ERK targets or opposing pathways.
- Further research is needed to understand the compensatory mechanisms in HePTP-deficient mice.