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Pragmin is one of the few mammalian proteins containing the Glu‐Pro‐Ile‐Tyr‐Ala ( EPIYA ) tyrosine‐phosphorylation motif that was originally discovered in the  Helicobacter pylori  CagA oncoprotein. Following delivery into gastric epithelial cells by type  IV  secretion and subsequent tyrosine phosphorylation at the  EPIYA  motifs, CagA serves as an oncogenic scaffold/adaptor that promiscuously interacts with  SH 2 domain‐containing mammalian proteins such as the Src homology 2 ( SH 2) domain‐containing protein tyrosine phosphatase‐2 ( SHP 2) and the C‐terminal Src kinase (Csk), a negative regulator of Src family kinases. Like CagA, Pragmin also forms a physical complex with Csk. In the present study, we found that Pragmin directly binds to Csk by the tyrosine‐phosphorylated  EPIYA  motif. The complex formation potentiates kinase activity of Csk, which in turn phosphorylates Pragmin on tyrosine‐238 (Y238), Y343, and Y391. As Y391 of Pragmin comprises the  EPIYA  motif, Pragmin–Csk interaction creates a feed‐forward regulatory loop of Csk activation. Together with the finding that Pragmin and Csk are colocalized to focal adhesions, these observations indicate that the Pragmin–Csk interaction, triggered by Pragmin  EPIYA  phosphorylation, robustly stimulates the kinase activity of Csk at focal adhesions, which direct cell‐matrix adhesion that regulates cell morphology and cell motility. As a consequence, expression of Pragmin and/or Csk in epithelial cells induces an elongated cell shape with elevated cell scattering in a manner that is mutually dependent on Pragmin and Csk. Deregulation of the Pragmin–Csk axis may therefore induce aberrant cell migration that contributes to tumor invasion and metastasis.

cancer science

C‐terminal Src kinase‐mediated  EPIYA  phosphorylation of Pragmin creates a feed‐forward C‐terminal Src kinase activation loop that promotes cell motility