Stabilization of Cyclin-Dependent Kinase 4 by Methionyl-tRNA Synthetase in p16^INK4a-Negative Cancer

Abstract

Although abnormal increases in the level or activity of cyclin-dependent kinase 4 (CDK4) occur frequently in cancer, the underlying mechanism is not fully understood. Here, we show that methionyl-tRNA synthetase (MRS) specifically stabilizes CDK4 by enhancing the formation of the complex between CDK4 and a chaperone protein. Knockdown of MRS reduced the CDK4 level, resulting in G0/G1 cell cycle arrest. The effects of MRS on CDK4 stability were more prominent in the tumor suppressor p16 INK4anegative cancer cells because of the competitive relationship of the two proteins for binding to CDK4. Suppression of MRS reduced cell transformation and the tumorigenic ability of a p16 INK4a-negative breast cancer cell line in vivo. Further, the MRS levels showed a positive correlation with those of CDK4 and the downstream signals at high frequency in p16 INK4a-negative human breast cancer tissues. This work revealed an unexpected functional connection between the two enzymes involving protein synthesis and the cell cycle.

Evolution of the multi-tRNA synthetase complex and its role in cancer

“…As mentioned earlier, AIMP2-DX2, a splicing variant that lacks exon 2 of AIMP2, is expressed in various cancers, compromising the tumor-suppressive activities of AIMP2 (40,41). In p16negative cancers, MRS appears to bind and stabilize CDK4, resulting in the promotion of the cell cycle (57). In light of the ARS connection to cancer, their cancer-specific expression, variant formation, and protein-protein interactions represent promising novel targets for developing anti-cancer therapeutics.…”

“…Induced by growth stimuli, MRS is translocated to the nucleoli to stimulate rRNA synthesis (15). MRS binds to and stabilizes CDK4 to promote the cell cycle in p16-negative cancers (57). QRS binds to apoptosis signal-regulating kinase 1 (ASK1) to regulate apoptosis in a glutamine-dependent manner (58).…”

“…Another example of ARS involvement in cancer-associated pathways is MRS, which is translocated to the nucleus to stimulate rRNA synthesis upon growth signals (15). It can also bind and stabilize CDK4 to promote the cell cycle (57). QRS binds to JBC REVIEWS: Multi-tRNA synthetase complex in cancer apoptosis signal-regulating kinase 1 (ASK1) to regulate apoptosis in a glutamine-dependent manner (58), and EPRS can repress VEGF-A synthesis at the translational suppression of its mRNA ( Fig.…”

Roles of Aminoacyl-tRNA Synthetases in Cancer

“…It is well known that the activity of cyclin-dependent kinase 4 (CDK4) is inhibited by p16 INK4a ( Cen et al, 2012 ; Liao et al, 2020 ). Intriguingly, MRS maintained the stability of CDK4 by interacting with CDK4 and heat shock protein 90 (HSP90), thereby regulating the cell cycle ( Kwon et al, 2018 ). Since MRS could compete with p16 INK4a for binding to CDK4, the stabilizing effect of MRS on CDK4 was more significant in p16 INK4a -negative breast cancer cells ( Kwon et al, 2018 ).…”

“…Intriguingly, MRS maintained the stability of CDK4 by interacting with CDK4 and heat shock protein 90 (HSP90), thereby regulating the cell cycle ( Kwon et al, 2018 ). Since MRS could compete with p16 INK4a for binding to CDK4, the stabilizing effect of MRS on CDK4 was more significant in p16 INK4a -negative breast cancer cells ( Kwon et al, 2018 ). Suppression of MRS reduced the tumorigenic ability of MDA-MB-231 cells in vivo , implying that MRS was involved in the development of breast cancer ( Kwon et al, 2018 ).…”