Suppression of lysyl-tRNA synthetase, KRS, causes incomplete epithelial-mesenchymal transition and ineffective cell-extracellular matrix adhesion for migration

Abstract

The cell-adhesion properties of cancer cells can be targeted to block cancer metastasis. Although cytosolic lysyl-tRNA synthetase (KRS) functions in protein synthesis, KRS on the plasma membrane is involved in cancer metastasis. We hypothesized that KRS is involved in cell adhesion-related signal transduction for cellular migration. To test this hypothesis, colon cancer cells with modulated KRS protein levels were analyzed for cell-cell contact and cell-substrate adhesion properties and cellular behavior. Although KRS suppression decreased expression of cell-cell adhesion molecules, cells still formed colonies without being scattered, supporting an incomplete epithelial mesenchymal transition. Noteworthy, KRS-suppressed cells still exhibited focal adhesions on laminin, with Tyr397-phopshorylated focal adhesion kinase (FAK), but they lacked laminin-adhesion-mediated extracellular signal-regulated kinase (ERK) and paxillin activation. KRS, p67LR and integrin α6β1 were found to interact, presumably to activate ERK for paxillin expression and Tyr118 phosphorylation even without involvement of FAK, so that specific inhibition of ERK or KRS in parental HCT116 cells blocked cell-cell adhesion and cell-substrate properties for focal adhesion formation and signaling activity. Together, these results indicate that KRS can promote cell-cell and cell-ECM adhesion for migration.

The role of tRNA synthetases in neurological and neuromuscular disorders

“…The cytosolic form of KARS is part of the multi‐tRNA synthetase complex (MSC) and involved in the housekeeping role; however, N‐terminal cleavage of KARS by caspase‐8 and an interaction with syntenin through its C‐terminal end leads to dissociation from the MSC complex and translocation to the plasma membrane where it associates with and stabilises a 67‐kDa laminin receptor (p67LR) . A study on HCT116 colon cancer cells showed that KARS localised to the plasma membrane is involved in cell–cell adhesion and more importantly suppression of KARS leads to impaired migratory abilities . Migration defects in CMT‐associated mutations may be involved in peripheral nerve lesions.…”

Bayesian Networks established functional differences between breast cancer subtypes

“…The interaction of KRS with 67LR enhances the membrane stability of 67LR, which in turn results in an increase laminin-dependent cell migration in metastasis [18]. KARS, causes incomplete epithelial-mesenchymal transition and ineffective cell-extracellular matrix adhesion for migration [22].…”

The pathophyiological role of aminoacyl-tRNA synthetases in digestive system diseases

“…KRS is reported to be upregulated in colorectal carcinoma than in healthy volunteers, and its expression is reduced after surgery, and has a prognostic potential for colorectal cancer ( Suh et al, 2020 ). In another study, suppression of KRS was reported to cause incomplete EMT (epithelial-mesenchymal transition) phenotype and impair the formation of focal adhesions in colon cancer cells ( Nam et al, 2016 ), which indicated that KRS might induce cell migration. Meanwhile, some previous articles reported that KRS interacted with 67LR (67-kDa laminin receptor) to promote cell migration.…”