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Molecular and Cellular Biology, March 2007, p. 2166-2179, Vol. 27, No. 6
0270-7306/07/$08.00+0     doi:10.1128/MCB.01234-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

T-Cell Protein Tyrosine Phosphatase, Distinctively Expressed in Activated-B-Cell-Like Diffuse Large B-Cell Lymphomas, Is the Nuclear Phosphatase of STAT6{triangledown}

Xiaoqing Lu,1 Jun Chen,1 R. Tedjo Sasmono,2,{dagger} Eric D. Hsi,3 Kristopher A. Sarosiek,4 Tony Tiganis,2 and Izidore S. Lossos1,4*

Sylvester Comprehensive Cancer Center, Division of Hematology-Oncology, Department of Medicine, Miami, Florida,1 Department of Biochemistry and Molecular Biology, Monash University, Melbourne, Victoria, Australia,2 Department of Clinical Pathology, Cleveland Clinic Foundation, Cleveland, Ohio,3 Department of Molecular and Cellular Pharmacology, University of Miami, Miami, Florida4

Received 7 July 2006/ Returned for modification 15 August 2006/ Accepted 21 December 2006

Diffuse large B-cell lymphomas (DLBCLs) consist of clinically distinct subtypes: germinal center B-cell (GCB)-like and activated-B-cell (ABC)-like tumors, characterized by long and short survival, respectively. We reported distinct interleukin 4 (IL-4) responsiveness and STAT6 signaling in these DLBCL subtypes. Increased nuclear dephosphorylation of phospho-STAT6 (pSTAT6) was observed in ABC-like tumors, which exhibited a different expression profile of protein tyrosine phosphatases (PTPs). Among the differentially expressed PTPs, only T-cell PTP (TCPTP) localizes to the nucleus. Herein, we report that the elevated expression of TCPTP in ABC- versus GCB-like DLBCL tumors is not due to the distinct ontogeny of these neoplasms but rather may be an acquired feature of the tumors. Moreover, we report that STAT6 may serve as a physiological nuclear substrate for TCPTP. We demonstrate interactions between endogenous TCPTP and STAT6 and delineate the domains responsible for the interaction. Overexpression of TCPTP ameliorates IL-4-induced STAT6 phosphorylation and associated gene transcription, whereas knockdown of endogenous TCPTP results in increased IL-4-induced STAT6 signaling. Moreover, we report that TCPTP protein levels may be increased in response to IL-4 and that TCPTP may serve in a negative feedback loop for the suppression of IL-4-induced signaling. Taken together, these results identify TCPTP as a physiological regulator of STAT6 phosphorylation and suggest that specific increases in TCPTP expression in ABC-like DLBCLs may contribute to the different biological characteristics of these tumors.

* Corresponding author. Mailing address: Department of Hematology and Oncology, Sylvester Comprehensive Cancer Center, University of Miami, 1475 NW 12th Ave. (D8-4), Miami, FL 33136. Phone: (305) 243-4785. Fax: (305) 243-4787. E-mail: ilossos{at}med.miami.edu.

{triangledown} Published ahead of print on 8 January 2007.

{dagger} Present address: Eijkman Institute for Molecular Biology, Jakarta, Indonesia.

Molecular and Cellular Biology, March 2007, p. 2166-2179, Vol. 27, No. 6
0270-7306/07/$08.00+0     doi:10.1128/MCB.01234-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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