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.
Highlights
Gastric cancer (GC) is a common malignancy of the digestive tract
We found that YES Proto-Oncogene 1 (YES1) OE significantly increased MGC-803 cell proliferation (Fig. 2D, left panel), colony formation (Fig. 2E, left panel), migration, and invasion ability (Fig. 2F, G, left panel). while YES1 KD significantly decreased AGS cell proliferation (Fig. 2D, right panel), Fig. 1 Erythropoietin-producing hepatocellular receptor A2 (EphA2) interacts with YES1 and phosphorylates YES1 at Tyr426 site
We analyzed the correlations between EphA2 and YES1 or annexin A2 (ANXA2) expression, and we found that the expression of EphA2 was positively correlated with YES1 expression in GC tissues (Fig. S9A), while it was not significantly related to ANXA2 staining (Fig. S9B)
Summary
Gastric cancer (GC) is a common malignancy of the digestive tract. There are more than one million new cases of GC every year worldwide, ranking the sixth in new cases. EphA2 is a key member of the receptor tyrosine kinase (RTK) family that plays important roles in multiple physiological and pathological processes. To investigate whether EphA2 phosphorylates and activates YES1, AGS and MGC-803 cells were transfected with HA-EphA2 expression plasmid, 48 h later cells were collected and subjected to IP with YES1 antibody to pull down the endogenous YES1 protein, followed by immunoblot using Phospho-SRC family Tyr416 antibody. In vitro kinase assay showed that active GSTEphA2 but not the nonactive BTN-EphA2 could phosphorylate YES1 at Tyr426 site (Fig. 1F). These results suggest that EphA2 interacts with YES1 and phosphorylates YES1 at Tyr426 site
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