Scientists identify a crucial new component in a pathway that malfunctions in cancer

One particular piece of cellular machinery that is known to malfunction in a number of cancers is a group of proteins called mTORC1. It coordinates many cellular functions by sensing external signals such as nutrients and growth factors and telling cells how to respond. Now, in a paper published October 7 in Molecular Cell, scientists at Sanford-Burnham Medical Research Institute have identified a new member of the mTORC1 team—a protein p62—that is crucial to the cell's response to dietary amino acids. This finding provides new information about mTORC1 and its role in cellular metabolism in both normal cells and cancer cells. What's more, it provides scientists with a new therapeutic target for cancers in which mTORC1 malfunctions.

p62 has several domains that can bind many different proteins to regulate important cellular function like growth and survival. Levels of p62 are elevated in many cancers. Researchers led by Maria Diaz-Meco, PhD, professor in Sanford-Burnham's NCI-designated Cancer Center looked for new p62 binding partners and found that p62 interacts with components of the well-known mTORC1 complex.

This study shows that amino acids trigger p62 to bind a protein raptor. In turn, p62 and raptor join the mTORC1 complex. Once these and other proteins are assembled in the lysosome, mTORC1 is activated.

When the team generated mice and cells that lack p62, they observed that mTORC1 no longer responded to amino acids. In other words, p62 is required for mTORC1 activation by amino acids. Moreover, it was only amino acid stimulation that required p62. Even without it, mTORC1 was still activated by other signals, such as insulin and growth factors.

The study shows how important cellular location is in the mTORC1 pathway. Now researchers would like to completely understand every step in this pathway. This information will allow to better understand cellular metabolism and its link to human diseases such as cancer.

This finding is the result of a long-time collaboration with the laboratory of another Sanford-Burnham professor, Jorge Moscat, PhD. Two laboratories have been unraveling the roles and functions of p62 since they first discovered it in 1998, as part of a complex network of proteins that play critical roles in the control of obesity and inflammation in cancer. These investigators believe that this network is a fertile ground for new therapeutic targets for obesity and type 2 diabetes, as well as cancer. Projects underway in their labs are aimed at pharmacologically targeting p62 and related proteins to generate new medicines for these diseases.

The study was funded by the USA National Cancer Institute, the USA Department of Defense, and the American Federation for Aging Research.

Source: European Society for Medical Oncology