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

Cancer Lett. 2019 Jul 10:454:70-77. doi: 10.1016/j.canlet.2019.04.011. Epub 2019 Apr 10.

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.

Keywords: Colon cancer; LMTK2; NF-κB.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Caco-2 Cells
  • Cell Line, Tumor
  • Cell Proliferation / physiology
  • Colonic Neoplasms / genetics
  • Colonic Neoplasms / metabolism*
  • Colonic Neoplasms / pathology
  • Cyclin D1 / biosynthesis
  • Cyclin D1 / genetics
  • Gene Knockdown Techniques
  • Glycogen Synthase Kinase 3 beta / metabolism
  • HCT116 Cells
  • Heterografts
  • Humans
  • Male
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Mice
  • Mice, Nude
  • NF-kappa B / metabolism*
  • Phosphorylation
  • Protein Phosphatase 1 / metabolism
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / metabolism*

Substances

  • CCND1 protein, human
  • Membrane Proteins
  • NF-kappa B
  • Cyclin D1
  • GSK3B protein, human
  • Glycogen Synthase Kinase 3 beta
  • LMTK2 protein, human
  • Protein Serine-Threonine Kinases
  • Protein Phosphatase 1