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Molecular and Cellular Biology, August 2002, p. 5662-5668, Vol. 22, No. 16
0270-7306/02/$04.00+0     DOI: 10.1128/MCB.22.16.5662-5668.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Identification of a Nuclear Stat1 Protein Tyrosine Phosphatase

Johanna ten Hoeve,1 Maria de Jesus Ibarra-Sanchez,2 Yubin Fu,1 Wei Zhu,3 Michel Tremblay,2 Michael David,3 and Ke Shuai1,4*

Department of Medicine,1 Department of Biological Chemistry, University of California—Los Angeles, Los Angeles, California 90095,4 Division of Biology, University of California—San Diego, La Jolla, California 92093,3 McGill Cancer Centre and Department of Biochemistry, McGill University, Montreal, Quebec H3G 1Y6, Canada2

Received 29 March 2002/ Returned for modification 7 May 2002/ Accepted 16 May 2002

Upon interferon (IFN) stimulation, Stat1 becomes tyrosine phosphorylated and translocates into the nucleus, where it binds to DNA to activate transcription. The activity of Stat1 is dependent on tyrosine phosphorylation, 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.

* Corresponding author. Mailing address: Department of Medicine, University of California—Los Angeles, Los Angeles, CA 90095. Phone: (310) 206-9168. Fax: (310) 825-6192. E-mail: kshuai{at}mednet.ucla.edu.

Molecular and Cellular Biology, August 2002, p. 5662-5668, Vol. 22, No. 16
0022-538X/02/$04.00+0     DOI: 10.1128/MCB.22.16.5662-5668.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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