PTPN18是细胞信号转导中的重要调控因子,参与细胞骨架重排,淋巴B细胞免疫应答等细胞活动。PTPN18通过去磷酸化其生理底物PSTPTP和HER2等，与化脓性无菌关节炎和癌症等疾病密切相关。阐明PTPN18的底物选择性和受调控机制既是目前的研究热点也具有重要科学意义。我们最近发现PTPN18选择性的调控HER2的C端酪氨酸磷酸化信息编码，以及SYK介导PTPN18与HER2的相互作用。基于这些研究基础，本课题将联合分子与细胞生物学方法，酶学和晶体结构手段，阐明PTPN18的底物选择性和对HER2磷酸化信息编码调节的分子机制，以及SYK对PTPN18的调控功能和机理。进一步，基于获得的PTPN18的底物选择性，我们还将联合生物信息学，以及改进陷阱分子技术，发现PTPN18的未知底物。优化的PTPN18陷阱技术将进一步发展为分子探针。

PTPN18 is an important regulator of cell signal transduction, participating in many cellular activities, such as cytoskeleton rearrangement, immune response of lymphocyte B cells. PTPN18 can specifically dephosphorylate PSTPIP and HER2, which are highly relevant factors of pyogenic sterile arthritis, pyoderma gangrenosum,and acne(PAPA) syndrome and cancer. Elucidation of PTPN18 substrate specificity and regulatory mechanism are important to extend our knowledge about human disease and PTP functions. Recently, our preliminary data demonstrates that (1) PTPN18 can specifically regulate distinct HER2 C-terminal phosphorylation sites, and (2) SYK mediates the interaction between HER2 and PTPN18. Based on these results, we are going to combine molecular and cellular approaches, enzymology and crystallographic methods, to elucidate the molecular mechanism of PTPN18 substrate specificity, its regulation on HER2 phosphorylation bar code, and how it was regulated by spleen tyrosine kinase(SYK). Further, based on PTPN18 substrate specificity, we are going to utilize bioinformatics and improved substrate trapping techniques to identify unknown PTPN18 substrates. The optimized PTPN18 substrate trapping mutant can also be developed to molecular trapping probes for further reasearch.