TC-PTP function in immune cells and its inhibition for potential therapeutic applications in human diseases.GCOE Program Seminar(Global Education Seminar)

Tyrosine phosphorylation is one of the most important protein modifications used to propagate cell signaling, and its levels is maintained by the opposite activities of protein tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPs). While a variety of PTKs have been characterized extensively, most PTPs have been poorly described to date. Surprisingly, recent findings on the PTP gene family clearly support that as many PTP members act as tumor suppressor than oncogenes (1). T cell protein tyrosine phosphatase (TC-PTP; gene name PTPN2) was one of the first PTPs to be identified. This enzyme is a classical non-receptor PTP and although named T-Cell-PTP (TC-PTP), it is ubiquitously expressed in embryonic and adult cells, with highest expression in hematopoietic cells. Particularly important is the recognition that TC-PTP negatively regulates Jak1 and Jak3 kinases downstream of several cytokines and chemokines pathways. More insight into the function of TC-PTP has been obtained through the study of TC-PTP-deficient mutant mice and cell lines that we generated, which identified TC-PTP as a key regulator of hematopoiesis and cytokine signaling. Indeed, Cool’s laboratory has recently identified mutations of TC-PTP in human T-ALL (2),
Among our recent findings is TC-PTP association to various inflammatory diseases including Intestinal Bowel Disease (IBD) and rheumatoid arthritis-like disease. Moreover, we showed that genetic or pharmacological inhibitions of TC-PTP in bone marrow cells provide a novel method to promote the expansion of selected populations of hematopoietic and endothelial stem cells. We will describe potential avenues to employ this approach in the treatment of various human diseases. 1) Inside the human cancer tyrosine phosphatome. Julien SG et al. Nat Rev Cancer. 2011, 11:35-49. 2) Kleppe M et al. Nat Genet. 2010 Jun;42:530-5.