PTPN9 is a non-receptor protein tyrosine phosphatase that functions as a negative regulator of receptor tyrosine kinase signaling and cellular homeostasis. Primary function: PTPN9 dephosphorylates multiple substrates including FGFR2 pY656/657, IGF1R pY1166, and the SNARE protein VTI1B, modulating their phosphorylation-dependent activities 123. Mechanism: PTPN9 operates through its sec.14p domain, which interacts with substrates via adaptor proteins like ACAP1, and regulates autophagosome formation through VTI1B dephosphorylation 13. Disease relevance: PTPN9 expression patterns vary contextually—downregulated in hepatocellular carcinoma and cervical carcinoma, where miR-96 suppresses its expression, but upregulated in esophageal squamous cell carcinoma and melanoma 4567. In cholangiocarcinoma, PTPN9 acts protectively by inhibiting FGFR2 and IGF1R signaling 12. Clinical significance: PTPN9 expression serves as a prognostic biomarker in multiple cancers and predicts therapeutic response to kinase inhibitors, with potential to enhance pemigatinib and surufatinib efficacy 12. PTPN9 genetic polymorphisms associate with alcohol-induced osteonecrosis susceptibility 8.