EphA2–YES1–ANXA2 pathway promotes gastric cancer progression and metastasis
Open Access
- 3 May 2021
- journal article
- research article
- Published by Springer Science and Business Media LLC in Oncogene
- Vol. 40 (20), 3610-3623
- https://doi.org/10.1038/s41388-021-01786-6
Abstract
Erythropoietin-producing hepatocellular receptor A2 (EphA2) is a key member of the receptor tyrosine kinase (RTK) family, while YES Proto-Oncogene 1 (YES1) is a non-receptor tyrosine kinase (nRTK) and annexin A2 (ANXA2) belongs to the calcium-dependent phospholipid-binding protein family annexins. Here, we show that EphA2, YES1, and ANXA2 form a signal axis, in which YES1 activated by EphA2 phosphorylates ANXA2 at Tyr24 site, leading to ANXA2 activation and increased ANXA2 nuclear distribution in gastric cancer (GC) cells. Overexpression (OE) of YES1 increases, while knockdown (KD) of YES1 or ANXA2 decreases GC cell invasion and migration in vitro and tumor growth in mouse models. Reexpression of wildtype (WT) rather than mutant ANXA2 (Tyr24F) in ANXA2 knockdown (ANXA2-KD) GC cells restores YES1-induced cell invasion and migration, while neither WT nor mutant ANXA2 (Tyr24F) can restore cell invasion and migration in YES1-KD GC cells. In addition, the activation of EphA2–YES1–ANXA2 pathway is correlated with poor prognosis. Thus, our results establish EphA2–YES1–ANXA2 axis as a novel pathway that drives GC invasion and metastasis, targeting this pathway would be an efficient way for the treatment of GC.Keywords
Funding Information
- National Natural Science Foundation of China (81974386)
- Research and Development program in Key Areas of Hunan Provinc
- Innovation Research Project of Central South University
- Natural Science Foundation of Hunan Provinc
This publication has 56 references indexed in Scilit:
- β-Catenin-Driven Cancers Require a YAP1 Transcriptional Complex for Survival and TumorigenesisCell, 2012
- Genotoxic Agents Promote the Nuclear Accumulation of Annexin A2: Role of Annexin A2 in Mitigating DNA DamagePLOS ONE, 2012
- Group B Streptococcus GAPDH Is Released upon Cell Lysis, Associates with Bacterial Surface, and Induces Apoptosis in Murine MacrophagesPLOS ONE, 2012
- Overexpression of EphA2 correlates with epithelial–mesenchymal transition-related proteins in gastric cancer and their prognostic importance for postoperative patientsMedical Oncology, 2011
- Eph receptors and ephrins in cancer: bidirectional signalling and beyondNature Reviews Cancer, 2010
- Annexin A2 Phosphorylation Mediates Cell Scattering and Branching Morphogenesis via Cofilin ActivationMolecular and Cellular Biology, 2008
- Annexin 2 Promotes the Formation of Lipid Microdomains Required for Calcium-regulated Exocytosis of Dense-Core VesiclesMolecular Biology of the Cell, 2005
- Autophosphorylation of Src and Yes blocks their inactivation by Csk phosphorylationOncogene, 1998
- Mapping of a regulatory important site for protein kinase C phosphorylation in the N-terminal domain of annexin IIBiochimica et Biophysica Acta (BBA) - Molecular Cell Research, 1996
- A tail of two src's: Mutatis mutandisCell, 1987