Interleukin 2 (IL-2) rapidly induces tyrosine phosphorylation of intracellular substrates, including the IL-2 receptor beta chain (IL-2R beta), Janus kinase 1 (Jak1), Jak3, signal transducer/activator of transcription proteins, and Shc, but the mechanism underlying dephosphorylation of these proteins is not known, The src homology 2 (SH2) containing tyrosine phosphatase 1 (SHP-1) is recruited by several hematopoietic surface receptors indicating that this phosphatase plays an important role as a regulator of signaling, We have found that IL-2 induces association of SHP-1 with the IL-2 receptor complex, and that once SHP-1 is recruited to the activated receptor it is able to decrease tyrosine phosphorylation of IL-2R beta and the associated tyrosine kinases Jak1 and Jak3, This dephosphorylation is specific as expression of a catalytically inactive form of SHP-1, or expression of the related phosphatase SHP-2 did not result In dephosphorylation of the IL-2 receptor components, Furthermore, we have found that SHP-1 expression is greatly decreased or undetectable in a number of IL-2 independent HTLV-1 transformed T cell lines that exhibit constitutive Jak/signal transducer/activator of transcription activation, In HTLV-I infected T cells, down-regulation of SHP-1 expression was also found to correlate with the acquisition of IL-2 independence. These observations suggest that SHP-1 normally functions to antagonize the IL-2 signal transduction pathway and that HTLV-1 infection and oncogenic transformation can lead to loss of SHP-1 expression resulting in constitutive activation of IL-2 regulated T cell responses.
Recruitment of SH2-containing protein tyrosine phosphatase SHP-1 to the interleukin 2 receptor; loss of SHP-1 expression in human T-lymphotropic virus type I-transformed T cells
Migone, T. S.; Cacalano, N. A.; Taylor, N.; Yi, T. L.; Waldmann, T. A.; Johnston, J. A.
Proceedings of the National Academy of Sciences of the United States of America
1998-03-31 / vol 95 / pages 3845-3850
activation; pathway; phosphorylation; signal-transduction; association; il-2 receptor; htlv-i; beta-chain; gamma(c) chain; kinase