Impaired phosphatase activity contributes to the persistent activation of STAT3 in tumors. Given that STAT family members with various or even opposite functions are often phosphorylated or dephosphorylated by the same enzymes, the mechanism for STAT3-specific dephosphorylation in cells remains largely unknown. Here, we report that GdX (UBL4A) promotesSTAT3dephosphorylation via mediating the interaction between TC45(the nuclear isoform of TC-PTP) and STAT3specifically. GdXstabilizes the TC45-STAT3 complex to bestow upon STAT3 an efficientdephosphorylation by TC45. Inasmuch, GdX suppresses tumorigenesis and tumor development by reducing the level of phospho-STAT3 (p-STAT3), whereas deletion of GdX results in a high level of p-STAT3 and accelerated colorectal tumorigenesis induced by AOM/DSS. Thus, GdX convertsTC45, a nonspecific phosphatase, into a STAT3-specific phosphatase by bridging an association between TC45 and STAT3.

Wang YM, Ning HX, Ren FL, Zhang YJ, Rong Y, Wang YY, Su FQ, Cai CG, Jin Z, Li ZY, Gong XQ, Zhai YG, Wang DJ, Jia BQ, Qiu Y, Tomita Y, Sung JJY, Yu J, Irwin DM, Yang X, Fu XY, Chin YE*, Chang ZJ*. (2014) GdX/UBL4A Specifically Stabilizes the TC45/STAT3 Association and Promotes Dephosphorylation of STAT3 to Repress Tumorigenesis. Molecular Cell, 53(5):752-765.