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Updated: Jul 21, 2025
Assessing Cellular Target Engagement by SHP2 PTPN11 Phosphatase Inhibitors
Published on: July 17, 2020
PTPN9 dephosphorylates FGFR2 pY656/657 through interaction with ACAP1 and ameliorates pemigatinib effect in
Liming Zhao1, Jialiang Liu1, Kangshuai Li1
1Department of General Surgery, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China.
Abstract And Aim:
Cholangiocarcinoma (CCA) is a highly aggressive and lethal cancer that originates from the biliary epithelium. Systemic treatment options for CCA are currently limited, and the first targeted drug of CCA, pemigatinib, emerged in 2020 for CCA treatment by inhibiting FGFR2 phosphorylation. However, the regulatory mechanism of FGFR2 phosphorylation is not fully elucidated.
Approach And Results:
Here we screened the FGFR2-interacting proteins and showed that protein tyrosine phosphatase (PTP) N9 interacts with FGFR2 and negatively regulates FGFR2 pY656/657 . Using phosphatase activity assays and modeling the FGFR2-PTPN9 complex structure, we identified FGFR2 pY656/657 as a substrate of PTPN9, and found that sec. 14p domain of PTPN9 interacts with FGFR2 through ACAP1 mediation. Coexpression of PTPN9 and ACAP1 indicates a favorable prognosis for CCA. In addition, we identified key amino acids and motifs involved in the sec. 14p-APCP1-FGFR2 interaction, including the "YRETRRKE" motif of sec. 14p, Y471 of PTPN9, as well as the PH and Arf-GAP domain of ACAP1. Moreover, we discovered that the FGFR2 I654V substitution can decrease PTPN9-FGFR2 interaction and thereby reduce the effectiveness of pemigatinib treatment. Using a series of in vitro and in vivo experiments including patient-derived xenografts (PDX), we showed that PTPN9 synergistically enhances pemigatinib effectiveness and suppresses CCA proliferation, migration, and invasion by inhibiting FGFR2 pY656/657 .
Conclusions:
Our study identifies PTPN9 as a negative regulator of FGFR2 phosphorylation and a synergistic factor for pemigatinib treatment. The molecular mechanism, oncogenic function, and clinical significance of the PTPN9-ACAP1-FGFR2 complex are revealed, providing more evidence for CCA precision treatment.
Insights
Protein tyrosine phosphatase N9 (PTPN9) inhibits FGFR2 phosphorylation, enhancing pemigatinib effectiveness against cholangiocarcinoma (CCA). PTPN9 and ACAP1 coexpression predicts favorable CCA prognosis, offering new avenues for precision treatment.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Cholangiocarcinoma (CCA) is an aggressive biliary tract cancer with limited systemic treatment options.
- Pemigatinib, a targeted therapy inhibiting FGFR2 phosphorylation, emerged in 2020, but its regulatory mechanisms require further elucidation.
- Understanding FGFR2 regulation is crucial for improving CCA treatment efficacy.
Purpose of the Study:
- To identify proteins interacting with FGFR2 and elucidate their role in CCA.
- To investigate the regulatory mechanism of FGFR2 phosphorylation and its impact on pemigatinib efficacy.
- To explore the clinical significance of identified interactions in CCA prognosis and treatment.
Main Methods:
- Screening of FGFR2-interacting proteins.
- Phosphatase activity assays and structural modeling of the FGFR2-PTPN9 complex.
- In vitro and in vivo experiments, including patient-derived xenografts (PDX) models.
Main Results:
- Protein tyrosine phosphatase N9 (PTPN9) identified as an interactor of FGFR2, negatively regulating its phosphorylation at pY656/657.
- PTPN9, via its sec. 14p domain and ACAP1 mediation, dephosphorylates FGFR2; coexpression of PTPN9 and ACAP1 correlates with favorable CCA prognosis.
- FGFR2 I654V substitution impairs PTPN9 interaction, reducing pemigatinib effectiveness; PTPN9 enhances pemigatinib efficacy, suppressing CCA progression.
Conclusions:
- PTPN9 acts as a negative regulator of FGFR2 phosphorylation and a synergistic factor for pemigatinib therapy in CCA.
- The PTPN9-ACAP1-FGFR2 complex's molecular mechanism and oncogenic function are elucidated.
- Findings provide a basis for precision treatment strategies in CCA, highlighting PTPN9's clinical significance.
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