Identification of a Nuclear Stat1 Protein Tyrosine Phosphatase

Upon interferon (IFN) stimulation, Stat1 becomes tyrosine phosphorylated and translocates into the nu-cleus, where it binds to DNA to activate transcription. The activity of Stat1 is dependent on tyrosine phos-phorylation, and its inactivation in the nucleus is accomplished by a previously unknown protein tyrosine phosphatase (PTP). We have now purified a Stat1 PTP activity from HeLa cell nuclear extract and identified it as TC45, the nuclear isoform of the T-cell PTP (TC-PTP). TC45 can dephosphorylate Stat1 both in vitro and in vivo. Nuclear extracts lacking TC45 fail to dephosphorylate Stat1. Furthermore, the dephosphorylation of IFN-induced tyrosine-phosphorylated Stat1 is defective in TC-PTP-null mouse embryonic fibroblasts (MEFs) and primary thymocytes. Reconstitution of TC-PTP-null MEFs with TC45, but not the endoplasmic reticulum (ER)-associated isoform TC48, rescues the defect in Stat1 dephosphorylation. The dephosphorylation of Stat3, but not Stat5 or Stat6, is also affected in TC-PTP-null cells. Our results identify TC45 as a PTP responsible for the dephosphorylation of Stat1 in the nucleus. A wide variety of cytokines and growth factors activate in-tracellular signaling events involving Janus kinases (JAKs) and signal transducers and activators of transcription (STATs). Li-gand activation of receptor-associated JAKs leads to tyrosin