PubMed Journals: Curr Biol

  Source:		PMID: 11909529

    		Curr Biol. 2002 Mar 19;12(6):446-53.
			The T cell protein tyrosine phosphatase
			is a negative regulator of janus family
			kinases 1 and 3.

			Simoncic PD(1), Lee-Loy A, Barber DL, Tremblay
			ML, McGlade CJ.

			Author Information
			(1) Department of Biochemistry and McGill
			Cancer Centre, McGill University, Montreal,
			Quebec, Canada.

			BACKGROUND: The immune response is regulated
			through a tightly controlled cytokine network.
			The counteracting balance between protein
			tyrosine kinase (PTK) and protein tyrosine
			phosphatase (PTP) activity regulates intracellular
			signaling in the immune system initiated by
			these extracellular polypeptides. Mice deficient
			for the T cell protein tyrosine phosphatase
			(TCPTP) display gross defects in the hematopoietic
			compartment, indicating a critical role
			for TCPTP in the regulation of immune homeostasis.
			To date, the molecular basis underlying
			this phenotype has not been reported. RESULTS:
			We have identified two members of the Janus
			family of tyrosine kinases (JAKs), JAK1
			and JAK3, as bona fide substrates of TCPTP.
			Inherent substrate specificity in the TCPTP-JAK
			interaction is demonstrated by the inability
			of other closely related PTP family members
			to form an in vivo interaction with the
			JAKs in hematopoietic cells. In keeping
			with a negative regulatory role for TCPTP
			in cytokine signaling, expression of TCPTP
			in T cells abrogated phosphorylation of
			STAT5 following interleukin (IL)-2 stimulation.
			TCPTP-deficient lymphocytes treated with
			IL-2 had increased levels of tyrosine-phosphorylated
			STAT5, and thymocytes treated with interferon
			(IFN)-alpha or IFN-gamma had increased
			tyrosine-phosphorylated STAT1. Hyperphosphorylation
			of JAK1 and elevated expression of iNOS
			was observed in IFN-gamma-treated, TCPTP-deficient,
			bone marrow-derived macrophages. CONCLUSIONS: We
			have identified JAK1 and JAK3 as physiological
			substrates of TCPTP. These results indicate
			a negative regulatory role for TCPTP in
			cytokine signaling and provide insight into
			the molecular defect underlying the phenotype
			of TCPTP-deficient animals.

			PMID: 11909529 [Indexed for MEDLINE]

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