Nat Commun: RNF167 targets the degradation of CASTOR1 and activates mTORC1 to promote tumor development

The serine/threonine kinase AKT is mutated in about 10% of cancers, which largely explains its carcinogenic effect in cancer.
In addition to mutations in the AKT gene, dysregulation of the upstream signaling pathways of growth factors can often activate AKT in cancer cells.

GSK3β, FOXO and TSC2 are the three main downstream genes of AKT, which can mediate the response of AKT to different stimuli and perform multiple functions.
Previous studies have shown that AKT-mediated phosphorylation and inhibition of TSC2 has been considered to be the main mechanism by which AKT activates mTORC1 (rapamycin complex 1).

mTORC1 is a central regulator of cell proliferation in response to growth factors and nutrients, and its expression is dysregulated in cancer.

Schematic diagram of related mechanisms

CASTOR1 (mTORC1 subunit 1) is a newly discovered cytoplasmic arginine sensor that responds to arginine and regulates the activity of mTORC1.

RNF167-mediated ubiquitination and AKT1-mediated phosphorylation promote the occurrence and development of breast cancer

Further studies have shown that several cell types with higher CASTOR1 expression are not sensitive to the regulation of arginine.

All in all, the results of the study revealed the relevant regulatory mechanism of mTORC1 and identified RNF167 as a therapeutic target for mTORC1 dysregulation-related diseases.