Lemur tyrosine kinase 2 acts as a positive regulator of NF-κB activation and colon cancer cell proliferation.

Abstract

Lemur tyrosine kinase 2 (LMTK2) belongs to both protein kinase and tyrosine kinase families. LMTK2 is less studied and little is known about its function. Here we demonstrate that LMTK2 modulates NF-κB activity and functions to promote colonic tumorigenesis. We found that LMTK2 protein was abundant in colon cancer cells and LMTK2 knockdown (LMTK2-KD) inhibited proliferation of colon cancer cells through inactivating NF-κB. In unstimulated condition, LMTK2 modulated NF-κB through inhibiting phosphorylation of p65 at Ser468. Mechanistically, LMTK2 phosphorylated protein phosphatase 1A (PP1A) to prevent PP1A from dephosphorylating p-GSK3β(Ser9). The p-GSK3β(Ser9) could not phosphorylate p65 at Ser468, which maintained the basal NF-κB activity. LMTK2 also modulated TNFα-activated NF-κB. LMTK2-KD repressed TNFα-induced IKKβ phosphorylation, IκBα degradation and NF-κB activation, implying that LMTK2 modulates TNFα-activated NF-κB via IKK. These results suggest that LMTK2 modulates basal and TNFα-induced NF-κB activities in different mechanisms. Animal studies show that LMTK2-KD suppressed colon cancer cell xenograft growth, decreased PP1A phosphorylation and increased p-p65(Ser468). Our results reveal the role and underlying mechanism of LMTK2 in colonic tumorigenesis and suggest that LMTK2 may serve as a potential target for chemotherapy of colon cancer.