Biochemistry Online: An Approach Based on Chemical Logic

CHAPTER 9 - SIGNAL TRANSDUCTION

D: mTOR and Nutrient Signaling

BIOCHEMISTRY - DR. JAKUBOWSKI

Last Update: 6/22/16

Learning Goals/Objectives for Chapter 9D:
After this reading, students will be able to

Describe the structure of mTOR Complex I and II;
Describe how rapamycin inhibits mTORC1;
Draw a cartoon of a generic protein kinase showing how its activity and specificity is regulated by activation and catalytic loops along with other protein binding partners;
Describe the structural differences between mTORC1 kinase and other kinases.
List typical substrates of mTORC1 and mTORC2;
Draw cartoons to show how Leu interacts with sestrin 2 and how this interaction activates mTORC1;
Describe how mTORC1 is recruited to lysosomal membranes and regulated by leucine through sestrin2, GATOR (GAP) proteins, Rag (small G) proteins, and Ragulator (GEF) proteins;
Explain how interactions of mTORC1 with Tsc 2/1 (GAP) proteins and Rheb (small G) proteins regulate mTORC1;
Describe how mTORC1 kinase activity is regulated by insulin through Akt and growth factors through MAP kinases;
Describe the different effects in metabolism mediated by AMPK and mTORC1

D1. Introduction to Nutrient Signaling

Imagine when you were in high school, you weighed 135 pounds (61 kg). Let's say its 50 years later and you still weighed 135 pounds. In the intervening years, think of how much food and liquid you consumed. In 2011, the USA Food and Drug Administration indicated that the average American consumed about 2000 pounds (907 kg) each year, including liquids other than drinking water. (Compare this to 365 kg for someone in Somalia!) So over 50 years you would have consumed 100,000 lbs (45,400 kg) of food, or 740 times your body weight. These numbers are essentially unchanged even if you gained one pound a year for a total of 50 pounds.

These figures suggest that we have an elaborate system that regulates how much we eat and how much weight we gain or lose. There are obvious times in our lives when we are growing and actively gaining body mass. Incoming food is not only processed into energy but also into net protein, lipid, carbohydrate and nucleic acid synthesis. This system obviously has become dysregulated in an ever increasing number of people with type II diabetes and obesity throughout the world. Obvious candidates for regulators in general of net body weight and in specific of protein and lipid synthesis are the nutrients we consume and store. Many systemic hormones and neurotransmitters are involved in hunger, satiety, and eating behavior. This chapter will not focus on those but rather on mechanisms of nutrient signaling pathways in growth which obviously requires new protein, lipid and nucleic acid synthesis for cell growth and division. Likewise, it will not focus on the nutrient signaling through hexosamines and UDP-GlcNAc.

A key player in these signaling pathways is mTORC (mammalian or mechanistic Target Of Rapamycin Complex). A key protein in this multiprotein complex is mTOR, a Ser/Thr kinase that regulates cell growth, division, protein synthesis, RNA synthesis (transcription) and even autophagy (the major process whereby cells die and their contents recycled for use). There are two physiologically relevant complexes of mTOR, mTORC1 and mTORC2. These two complex have been called the master regulators of metabolic and growth processes.

mTORC1 activates protein, lipid and nucleotide synthesis, all required for cell growth and division; it is inhibited by rapamycin. For activation it needs two obvious conditions: energy and growth factors. In addition it needs amino acids.
mTORC2 activates many processes through phosphorylation; it is not inhibited by rapacmycin.

What is Rapamycin? It sounds like an antibiotic but it is actually an antifungal agent produced by certain bacteria as a defense against fungal (eukaryotic) pathogens. It blocks cell division in fungi by stopping cell growth. The cell cycle consists of the following general sequential steps: (Go-G1)-->S -->G2-->M--> G1. Gap 0 (Go) is a quiescent phase outside of the cycle. In G1, cells are growing and preparing for DNA synthesis which occurs in S phase. After DNA replication/synthesis (S phase), cells grow again and prepare for mitotic cell division (M phase). Rapamycin traps fungal cells in G1 phase. It also traps mammalian cells, and in particular immune lymphocytes in G1 as well, preventing lymphocytes from dividing. Hence rapamycin has been used to prevent rejection of transplanted tissue as it suppresses the immune system. Rapamycin inhibits mTORC1. That it inhibits mTOR is consistent with its immunosuppressive (antigrowth and antiproliferative) effects.

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