Transmembrane 4 L Six Family Member 5 Senses Arginine for mTORC1 Signaling

By Prof. Sun Choi (sunchoi@ewha.ac.kr)
Department of Pharmacy

Transmembrane 4 L six family member 5 (TM4SF5) is a transmembrane protein known to interact with other TM4SFs, signaling proteins, and integrins. These interactions lead to uncontrollable cell growth and proliferation, eventually resulting in critical conditions, namely fibrosis and cancer. Recently, we have identified TM4SF5 as an arginine sensor for the mechanistic target of rapamycin complex (mTORC1) activation and subsequent phosphorylation of its downstream effectors. TM4SF5 translocates to lysosomes based on arginine supply, sensing and enabling lysosomal arginine efflux to cytosol for mTORC1/S6K1 activation; and thus, arginine-auxotroph in hepatocellular carcinoma can be targeted by blocking arginine sensing using anti-TM4SF5 reagents. The functions of mTORC1 are significantly affected when conserved residues in long extracellular loop region of TM4SF5 were mutated, supporting the involvement of TM4SF5 in this pathway.

TM4SF5 is overexpressed in various cancer types, especially liver cancer. Clinical reports on hepatocellular carcinoma (HCC) reveal that HCC depends on cytosolic arginine due to inactivated enzymes related to arginine metabolism (i.e., arginine-auxotroph) for cell signaling and growth. Thus, extracellular arginine from diet supplies and lysosomal arginine from autophagy-mediated protein degradations would be transported to the cytosol. In addition, lysosomal arginine at physiological levels can be transported to the cytosol, leading to activation of mTORC1 and S6K1 for protein translation during cell growth. Many laboratories have tried to identify the arginine sensor on lysosomal membranes that would recognize and bind arginine in ruins, since a putative sensor (SLC38A9) appeared to have an affinity (4~39 mM) much higher than the physiological arginine levels (<400 μM). In our research, we found TM4SF5 as the lysosomal arginine sensor binding at 10~37 μM during arginine-mediated mTORC1/S6K1 activation, and that anti-TM4SF5 reagents (e.g., TSAHC) can cause HCC death due to arginine-starvation.

 

 

* Related Article
J.W. Jung, S.J.Y. Macalino, M. Cui, J.E. Kim, H.J. Kim, D.G. Song, S.H. Nam, S. Kim, S. Choi, J.W. Lee, Transmembrane 4 L Six Family Member 5 Senses Arginine for mTORC1 Signaling, Cell Metabolism, 2019, 29(6), 1306-1319. http://www.ncbi.nlm.nih.gov/pubmed/30956113

* Online news introducing the article
https://biz.chosun.com/site/data/html_dir/2019/04/05/2019040500842.html