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<p>Protein tyrosine phosphatase type IVA 3 (PTP4A3) is implicated in the metastasis of hepatocellular carcinoma (HCC), yet its precise regulatory mechanisms remain elusive. This study aimed to identify the interacting substrates and underlying mechanisms of PTP4A3 to inform the optimization of PTP4A3-targeted therapies in HCC. Using the TurboID system and protein mass spectrometry, over 500 candidate substrates for PTP4A3 were identified. A direct interaction between PTP4A3 and epidermal growth factor receptor (EGFR) was also validated. Ti-IMAC protein phosphorylation mass spectrometry revealed that PTP4A3 dephosphorylates Thr693 of EGFR. This dephosphorylation event enhanced EGFR-ERBB2 heterodimerization, leading to increased RhoA-GTPase activation, cell motility, and cytoskeletal rearrangement. EGFR/ERBB2 inhibition effectively suppressed PTP4A3-driven metastasis both in vitro and in vivo. This study reveals a novel mechanism by which PTP4A3 promotes HCC metastasis via direct dephosphorylation of EGFR at Thr693. Lapatinib, an inhibitor of EGFR/ERBB2, effectively suppressed PTP4A3-driven HCC metastasis, offering a potential therapeutic strategy for HCC patients with high PTP4A3 expression.</p><p></p>

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PTP4A3 dephosphorylates EGFR to promote metastasis and enhance sensitivity to lapatinib in hepatocellular carcinoma

  • 期刊论文

  • 发表日期：

    2026年7月8日

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  • Yuyang Du,
  • Xiao-Feng Zhang,
  • Shasha Wu,
  • Jingyi Zheng,
  • Han Gao,
  • Shaoyan Xi,
  • Liangzhan Sun,
  • Jingsong Yan,
  • Fenfen Wang,
  • Yanchen Wang,
  • Hui Yang,
  • Xijun Ou,
  • Ming Liu,
  • Jia Xiao,
  • Qiong Pan,
  • Yan Li

摘要

Protein tyrosine phosphatase type IVA 3 (PTP4A3) is implicated in the metastasis of hepatocellular carcinoma (HCC), yet its precise regulatory mechanisms remain elusive. This study aimed to identify the interacting substrates and underlying mechanisms of PTP4A3 to inform the optimization of PTP4A3-targeted therapies in HCC. Using the TurboID system and protein mass spectrometry, over 500 candidate substrates for PTP4A3 were identified. A direct interaction between PTP4A3 and epidermal growth factor receptor (EGFR) was also validated. Ti-IMAC protein phosphorylation mass spectrometry revealed that PTP4A3 dephosphorylates Thr693 of EGFR. This dephosphorylation event enhanced EGFR-ERBB2 heterodimerization, leading to increased RhoA-GTPase activation, cell motility, and cytoskeletal rearrangement. EGFR/ERBB2 inhibition effectively suppressed PTP4A3-driven metastasis both in vitro and in vivo. This study reveals a novel mechanism by which PTP4A3 promotes HCC metastasis via direct dephosphorylation of EGFR at Thr693. Lapatinib, an inhibitor of EGFR/ERBB2, effectively suppressed PTP4A3-driven HCC metastasis, offering a potential therapeutic strategy for HCC patients with high PTP4A3 expression.