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LMTK2 Inhibits Metastasis of Colon Cancer Cells Through p38 MAPK
Jie Lun1,2, Jinzhao Zhang3, Jianxin Xu1,2
1Department of Oncology, The Affiliated Hospital of Qingdao University, Qingdao Cancer Institute, Qingdao, China.
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.
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