Switching of the substrate specificity of protein tyrosine phosphatase N12 by cyclin-dependent kinase 2 phosphorylation orchestrating 2 oncogenic pathways.

摘要: The protein tyrosine phosphatase nonreceptor type 12 (PTPN12) is a multifunctional and has elicited much research attention because its decreased level been associated with poor prognosis of several types cancers. Recently, we have solved the crystal structure domain PTPN12, which disclosed specific PTPN12-insert-loop harboring cyclin-dependent kinase 2 (CDK2) phosphorylation site. However, functional significance this undefined. In present study, found that S19 site PTPN12 by CDK2 discharged antitumor activity down-regulation inhibitory role in cell migration, but not affecting other regulatory functions. Phosphorylation at changed substrate interface, doing so, selectively toward human epidermal growth factor receptor (HER2)- pY1196 site, HER2 sites or known substrates. A further in-depth mechanism study revealed impaired recruitment serine/threonine-protein 1 (PAK1) to HER2, resulted blockade HER2-pY1196-PAK1-T423 signaling pathway, thus increased tumor motility. Taken together, our results identified new phosphorylation-based recognition CDK2, orchestrated crosstalk between oncogenic pathways. newly governing selectivity particular was previously unappreciated exemplifies how phospho-network precisely controlled different cellular contexts.-Li, H., Yang, D., Ning, S., Xu, Y., F., Yin, R., Feng, T., Han, Guo, L., Zhang, P., Qu, W., Song, C., Xiao, Zhou, Z., Sun, J.-P., Yu, X. Switching specificity N12 orchestrating