Targeting pSTAT3 has becoming an important strategy for cancer therapies since hyper-phosphorylation of STAT3 at tyrosine residues is associated with various types of human cancers including breast cancer. The hyper-phosphorylated STAT3 was caused by either the over-activation of tyrosine kinases or the impaired function of tyrosine phosphatases. While many kinases have been reported to activate STAT3 in tumors, it is still interesting to identify a direct STAT3 phosphatase. In this study, we found that PTPMeg2 is a strong phosphatase directly interacting with STAT3 and mediating STAT3 dephosphorylation.
We have presented several lines of evidence demonstrating STAT3 is a substrate of PTPMeg2. First, PTPMeg2 physically and pathologically interacts with STAT3. Significantly, PTPMeg2 exhibits a strong affinity for pSTAT3 and STAT3. Next, PTPMeg2 dephosphorylated pSTAT3 in time- and dose-dependent manners. Third, the catalytically inactive mutant of PTPMeg2 lost the negative role in pSTAT3. Fourth, deletion of the lipid-binding domain of PTPMeg2 has no effect on the dephosphorylation. On the contrary, depleting PTPMeg2 enhances the level of pSTAT3 in cells and results in the cell proliferation and tumor growth in nude mice. Consistent with the biochemistry and cellular biology data, we observed that the negative correlation between the expression of PTPMeg2 and pSTAT3 in human breast cancer samples. All the results are consistent and intercomparable in demonstrating the role of PTPMeg2 in regulation of STAT3 activity in the breast cancer. However, we can not exclude the possibility that PTPMeg2 may target other substance. In this study, we demonstrated that the inhibitory role of PTPMeg2 on tumor growth was mainly through dephosphorylation of STAT3.
Previous studies reported that several PTPs such as PTPN1, PTPN3, and PTPN6 have oncogenic properties but other PTPs including PTPN12 have tumor suppressor features. In this study, we found that PTPMeg2 is a tumor repressor preferentially dephosphorylating STAT3. We have used several cell models to demonstrate that enforced expression of PTPMeg2 inhibited tumor cell growth and depletion of PTPMeg2 resulted in enlarged tumors. Intriguingly we found that the expression of PTPMeg2 was negative in human breast cancer while it remained high in the peritumoral tissues. This expression pattern is similar to that of PTPN7 and PTPN13, which were reported to be at a global loss in a wide range of cancers including breast, kidney, and esophageal cancers. Recently, PTPN13 was reported to loss its activity through somatic mutations, allelic loss, or promoter methylation in some tumors. Whether PTPMeg2 has such a kind of mutations in tumors remains unclear.
It has reported that PTPL1/PTPN13 regulated breast cancer cell aggressiveness through a direct inactivation of Src kinase and PTPN12 inhibits breast cancer metastasis through multiple targets including EGFR1, Her2 and Src kinase. A previous study reported that PTPMeg2 targets EGFR and Her2. In this study, we found that PTPMeg2 directly interacts with STAT3. Interestingly, when we used v-Src to activate STAT3 phosphorylation, we observed that PTPMeg2 strongly mediated dephosphorylation of STAT3 (Figure 5). However, we did not observe any interaction of v-Src with PTPMeg2. This result implies that PTPMeg2 directly targets STAT3 activated by v-Src. Since STAT3 associates with EGFR or Her2, it is possible that PTPMeg2 interacts with the STAT3/EGFR complex, as observed by a previous study. Whether the interaction of PTPMeg2 with STAT3 requires other partners will be an interesting question in future studies.
Another interesting observation is that PTPMeg2 mediates dephosphorylation of STAT3 at residue Try705 while is has no effect of the phosphorylation of STAT3 at residue Ser727. This seems reasonable since PTPMeg2 is in the family of protein tyrosine phosphatases. We predict that the dephosphorylation of STAT3 at other non tyrosine residues is likely mediated by other phosphatases to be further identified.
Breast Cancer Res. 2012;14(2):R38 © 2012 BioMed Central, Ltd.
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