RNF167 and CASTOR1 as Novel mTOR Targets

Researchers also demonstrated that AKT and RNF167-mediated CASTOR1 degradation activates mTORC1 and promotes breast cancer progression. AKT-mediated phosphorylation of CASTOR1 significantly increases its binding to RNF167, revealing a novel mTORC1 regulating mechanism and potential new therapeutic targets for mTORC1-dysregulated diseases. 

Description

Several devastating diseases including cancer, diabetes, and age-related issues have been linked to dysregulation of mTORC1, a central controller of cell proliferation in response to growth factors and nutrients. The activity of mTORC1 is repressed by cytosolic arginine sensor for mTORC1 subunit 1, or CASTOR1. Low CASTOR1 expression is a poor prognosis marker for ten types of cancer, while high expression of the RNF167, a ligase that targets CASTOR1 for degradation, has been identified as a poor prognosis marker for five types of cancer.

Applications

• Treating diseases linked to dysregulation of mTORC1
• Disease prognosis
• CASTOR-1 phospho-specific antibody is capable of detecting strong staining in more than ten types of cancer compared to controls, which can detect almost no staining, indicating its use as a potential biomarker

Advantages

• Entirely novel method of regulating mTORC1

Invention Readiness

In vivo data

IP Status

https://patents.google.com/patent/US20230357430A1

Related Publication(s)

Li, T., Wang, X., Ju, E., da Silva, S. R., Chen, L., Zhang, X., Wei, S., & Gao, S.-J. (2021). RNF167 activates mTORC1 and promotes tumorigenesis by targeting CASTOR1 for ubiquitination and degradation. Nature Communications, 12(1). https://doi.org/10.1038/s41467-021-21206-3

Yao, S., Jia, X., Wang, F., Sheng, L., Song, P., Cao, Y., Shi, H., Fan, W., Ding, X., Gao, S.-J., & Lu, C. (2021). CircRNA ARFGEF1 functions as a ceRNA to promote oncogenic KSHV-encoded viral interferon regulatory factor induction of cell invasion and angiogenesis by upregulating glutaredoxin 3. PLOS Pathogens, 17(2), e1009294. https://doi.org/10.1371/journal.ppat.1009294

Li, T., Ju, E., & Gao, S.-J. (2019). Kaposi sarcoma–associated herpesvirus miRNAs suppress CASTOR1-mediated mTORC1 inhibition to promote tumorigenesis. Journal of Clinical Investigation, 129(8), 3310–3323. https://doi.org/10.1172/jci127166