LMTK2 Inhibits Metastasis of Colon Cancer Cells Through p38 MAPK

ABSTRACT

Metastasis is the leading cause of death in patients with colon cancer. Although Lemur tyrosine kinase 2 (LMTK2) has been implicated in cell proliferation, its role in metastasis is unclear. In this study, we found that low LMTK2 expression correlates with metastatic status (M1 stage) and a higher metastasis rate in a large colon cancer cohort. Additionally, LMTK2 expression is negatively correlated with pro‐metastatic genes and positively correlated with metastasis suppressors, a pattern that was validated in 50 clinical colon cancer specimens. Functional studies demonstrated that LMTK2 potently inhibits cell migration and invasion in vitro and suppresses metastasis in a mouse model in vivo. Mechanistically, LMTK2 disrupts the interaction between p38 MAPK and its upstream kinases MKK3/6, thereby inhibiting p38 activation and subsequent cell migration and invasion. Notably, the kinase‐deficient LMTK2 (K168R) mutant also suppresses p38 phosphorylation and impedes cell migration and invasion. These results uncover a novel anti‐metastatic function of LMTK2, which acts through inhibition of p38 independently of its kinase activity.