Anti-LMTK2 monoclonal antibody, clone FQS8947(3)

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-kappa B 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-kappa B. In unstimulated condition, LMTK2 modulated NF-kappa B through inhibiting phosphorylation of p65 at Ser468. Mechanistically, LMTK2 phosphorylated protein phosphatase 1A (PP1A) to prevent PP1A from dephosphorylating p-GSK3 beta(Ser9). The p-GSK3 beta(Ser9) could not phosphorylate p65 at Ser468, which maintained the basal NF-kappa B activity. LMTK2 also modulated TNF alpha-activated NF-kappa B. LMTK2-KD repressed TNF alpha-induced IKK beta phosphorylation, I kappa B alpha degradation and NF-kappa B activation, implying that LMTK2 modulates TNF alpha-activated NF-kappa B via UGC These results suggest that LMTK2 modulates basal and TNF alpha-induced NF-kappa B 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.

Cystic fibrosis transmembrane conductance regulator (CFTR) is a Cl- -selective ion channel expressed in fluid-transporting epithelia. Lemur tyrosine kinase 2 (LMTK2) is a transmembrane protein with serine and threonine but not tyrosine kinase activity. Previous work identified CFTR as an in vitro substrate of LMTK2, suggesting a functional link. Here we demonstrate that LMTK2 co-immunoprecipitates with CFTR and phosphorylates CFTR-Ser737 inhumanairway epithelial cells. LMTK2knockdown or expression of inactive LMTK2 kinase domain increases cell surface density of CFTR by attenuating its endocytosis in human airway epithelial cells. Moreover, LMTK2 knockdown increases Cl- secretion mediated by the wild-type and rescued Delta F508-CFTR. Compared with the wild-type CFTR, the phosphorylation-deficient mutant CFTR-S737A shows increased cell surface density and decreased endocytosis. These results demonstrate a novel mechanism of the phospho-dependent inhibitory effect of CFTR-Ser(737) mediated by LMTK2 via endocytosis and inhibition of the cell surface density of CFTRCl- channels. These data indicate that targeting LMTK2 may increase the cell surface density of CFTR Cl- channels and improve stability of pharmacologically rescued Delta F508-CFTR in patients with cystic fibrosis.