TY - JOUR
T1 - Receptor-associated constitutive protein tyrosine phosphatase activity controls the kinase function of JAK1
AU - Haque, S. Jaharul
AU - Wu, Qian
AU - Kammer, Winfried
AU - Friedrich, Karlheinz
AU - Smith, Jonathan M.
AU - Kerr, Ian M.
AU - Stark, George R.
AU - Williams, Bryan R.G.
PY - 1997/8/5
Y1 - 1997/8/5
N2 - Exposure of cells to protein tyrosine phosphatase (PTP) inhibitors causes an increase in the phosphotyrosine content of many cellular proteins. However, the level at which the primary signaling event is affected is still unclear. We show that Jaks are activated by tyrosine phosphorylation in cells that are briefly exposed to the PTP inhibitor pervanadate (PV), resulting in tyrosine phosphorylation and functional activation of Stat6 (in addition to other Stats). Mutant cell lines that lack Jak1 activity fail to support PV- mediated [or interleukin 4 (IL-4)-dependent] activation of Stat6 but can be rescued by complementation with functional Jak1. The docking sites for both Jak1 and Stat6 reside in the cytoplasmic domain of the IL-4 receptor α- chain (IL-4Rα). The glioblastoma-derived cell lines T98G, GRE, and M007, which do not express the IL-4Rα chain, fail to support Stat6 activation in response to either IL-4 or PV. Complementation of T98G cells with the IL- 4Rα restores both PV-mediated and IL-4-dependent Stat6 activation. Murine L929 cells, which do not express the γ common chain of the IL-4 receptor, support PV-mediated but not IL-4-dependent Stat6 activation. Thus, Stat6 activation by PV is an IL-4Rα-mediated, Jak1-dependent event that is independent of receptor dimerization. We propose that receptor-associated constitutive PTP activity functions to down-regulate persistent, receptor- linked kinase activity. Inhibition or deletion of PTP activity results in constitutive activation of cytokine signaling pathways.
AB - Exposure of cells to protein tyrosine phosphatase (PTP) inhibitors causes an increase in the phosphotyrosine content of many cellular proteins. However, the level at which the primary signaling event is affected is still unclear. We show that Jaks are activated by tyrosine phosphorylation in cells that are briefly exposed to the PTP inhibitor pervanadate (PV), resulting in tyrosine phosphorylation and functional activation of Stat6 (in addition to other Stats). Mutant cell lines that lack Jak1 activity fail to support PV- mediated [or interleukin 4 (IL-4)-dependent] activation of Stat6 but can be rescued by complementation with functional Jak1. The docking sites for both Jak1 and Stat6 reside in the cytoplasmic domain of the IL-4 receptor α- chain (IL-4Rα). The glioblastoma-derived cell lines T98G, GRE, and M007, which do not express the IL-4Rα chain, fail to support Stat6 activation in response to either IL-4 or PV. Complementation of T98G cells with the IL- 4Rα restores both PV-mediated and IL-4-dependent Stat6 activation. Murine L929 cells, which do not express the γ common chain of the IL-4 receptor, support PV-mediated but not IL-4-dependent Stat6 activation. Thus, Stat6 activation by PV is an IL-4Rα-mediated, Jak1-dependent event that is independent of receptor dimerization. We propose that receptor-associated constitutive PTP activity functions to down-regulate persistent, receptor- linked kinase activity. Inhibition or deletion of PTP activity results in constitutive activation of cytokine signaling pathways.
KW - Interleukin 4 receptor
KW - Janus kinase
KW - Pervanadate
KW - Protein tyrosine kinase
KW - Signal transducer and activator of transcription
UR - http://www.scopus.com/inward/record.url?scp=0030795790&partnerID=8YFLogxK
U2 - 10.1073/pnas.94.16.8563
DO - 10.1073/pnas.94.16.8563
M3 - Article
C2 - 9238016
AN - SCOPUS:0030795790
SN - 0027-8424
VL - 94
SP - 8563
EP - 8568
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 16
ER -