ArticleCell research2014
The catalytic region and PEST domain of PTPN18 distinctly regulate the HER2 phosphorylation and ubiquitination barcodes.
Article in Cell research, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 52 papers.
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Who cites it
52 citing papers in PubMed, 92 citations in OpenAlex.
- PTPN18 functions as a tumor suppressor in breast cancer by negatively regulating cyclin E.International journal of oncology · 2026Article
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- The R451 site is critical for PTPN18 to exert tumor suppressive effects in breast cancer through the negative regulatory interacting protein fibrillarin.Cell death & disease · 2026Article
- The therapeutic effect of DX2 inhibition in nicotine-induced lung cancer progression.Molecular therapy. Oncology · 2024Article
- Promotion of stem cell-like phenotype of lung adenocarcinoma by FAM83A via stabilization of ErbB2.Cell death & disease · 2024Article
- Ultrasonic-responsive piezoelectric stimulation enhances sonodynamic therapy for HER2-positive breast cancer.Journal of nanobiotechnology · 2024Article
- The impact of nitric oxide on HER family post-translational modification and downstream signaling in cancer.Frontiers in physiology · 2024Review
- Protein tyrosine phosphatase PTPH1 potentiates receptor tyrosine kinase HER2 oncogenesis via a PDZ-coupled and phosphorylation-driven scaffold.American journal of cancer research · 2024Article
- Function, mechanism and drug discovery of ubiquitin and ubiquitin-like modification with multiomics profiling for cancer therapy.Acta pharmaceutica Sinica. B · 2023Review
- Dysregulated ceramides metabolism via PTPN11 exposes a metabolic vulnerability to breast cancer metastasis.Medical oncology (Northwood, London, England) · 2023Article
- Preclinical and Basic Research Strategies for Overcoming Resistance to Targeted Therapies in HER2-Positive Breast Cancer.Cancers · 2023Review
- CMTM6 overexpression confers trastuzumab resistance in HER2-positive breast cancer.Molecular cancer · 2023Article
- Nuclear import of PTPN18 inhibits breast cancer metastasis mediated by MVP and importin β2.Cell death & disease · 2022Article
- Reply to Schramm, L. Comment on "Li et al.Diagnostics (Basel, Switzerland) · 2022Article
- Pan-cancer analyses of classical protein tyrosine phosphatases and phosphatase-targeted therapy in cancer.Frontiers in immunology · 2022Article
- Hereditable variants of classical protein tyrosine phosphatase genes: Will they prove innocent or guilty?Frontiers in cell and developmental biology · 2022Review
- PTPN18 Stimulates the Development of Ovarian Cancer by Activating the PI3K/AKT Signaling.Evidence-based complementary and alternative medicine : eCAM · 2022Article
- Sortilin-related receptor is a druggable therapeutic target in breast cancer.Molecular oncology · 2022Article
- PTPN18 promotes colorectal cancer progression by regulating the c-MYC-CDK4 axis.Genes & diseases · 2021Article
- PTP-MEG2 regulates quantal size and fusion pore opening through two distinct structural bases and substrates.EMBO reports · 2021Article
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19 authors at 4 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The tyrosine phosphorylation barcode encoded in C-terminus of HER2 and its ubiquitination regulate diverse HER2 functions. PTPN18 was reported as a HER2 phosphatase; however, the exact mechanism by which it defines HER2 signaling is not fully understood. Here, we demonstrate that PTPN18 regulates HER2-mediated cellular functions through defining both its phosphorylation and ubiquitination barcodes. Enzymologic characterization and three crystal structures of PTPN18 in complex with HER2 phospho-peptides revealed the molecular basis for the recognition between PTPN18 and specific HER2 phosphorylation sites, which assumes two distinct conformations. Unique structural properties of PTPN18 contribute to the regulation of sub-cellular phosphorylation networks downstream of HER2, which are required for inhibition of HER2-mediated cell growth and migration. Whereas the catalytic domain of PTPN18 blocks lysosomal routing and delays the degradation of HER2 by dephosphorylation of HER2 on pY(1112), the PEST domain of PTPN18 promotes K48-linked HER2 ubiquitination and its rapid destruction via the proteasome pathway and an HER2 negative feedback loop. In agreement with the negative regulatory role of PTPN18 in HER2 signaling, the HER2/PTPN18 ratio was correlated with breast cancer stage. Taken together, our study presents a structural basis for selective HER2 dephosphorylation, a previously uncharacterized mechanism for HER2 degradation and a novel function for the PTPN18 PEST domain. The new regulatory role of the PEST domain in the ubiquitination pathway will broaden our understanding of the functions of other important PEST domain-containing phosphatases, such as LYP and PTPN12.
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