The GATOR Complex: How It Controls Cell Growth

Within our cells, a network of proteins monitors nutrient availability to guide a cell’s decision to either grow or conserve resources. At the heart of this system is a group of proteins known as the GATOR complex, which functions as a gatekeeper for cell growth by sensing the levels of amino acids. By detecting these molecular cues, the GATOR complex ensures that cells only commit to the energy-intensive processes of growth and division when materials are present. The complex acts as a switch, toggling between states of active proliferation and periods of maintenance and recycling.

The Two Sides of GATOR

The GATOR complex is composed of two distinct subcomplexes that work in opposition to one another to control cell growth. These are known as GATOR1 and GATOR2, each with a specific role in the nutrient-sensing pathway. Their interaction forms a regulatory system that responds dynamically to the changing nutritional environment inside the cell.

GATOR1 functions as the primary “brake” on cell growth. When active, it directly halts the signals that promote cellular expansion and proliferation. This inhibitory subcomplex is made up of three core protein components: DEPDC5, NPRL2, and NPRL3.

In contrast, GATOR2 acts as the “sensor” and the regulator of the brake. Its main purpose is to detect the presence of amino acids and, in response, to inhibit the GATOR1 complex. This releases the brake and permits growth to proceed. GATOR2 is a larger assembly, composed of five proteins:

• Mios
• WDR24
• WDR59
• Seh1L
• Sec13

The Mechanism of Amino Acid Sensing

The process of detecting amino acids occurs at a specific location within the cell: the surface of the lysosome. The lysosome is the cell’s recycling center, as it breaks down and processes waste materials. Its surface provides a platform where the components of the growth-control machinery can assemble and interact.

The GATOR complex does not sense all amino acids directly. Instead, it relies on other specialized sensor proteins to relay information about two specific amino acids: leucine and arginine. When leucine is abundant, it is detected by a sensor protein named Sestrin2. Similarly, high levels of arginine are detected by a different sensor called CASTOR1.

Once these sensor proteins detect their respective amino acids, they physically bind to the GATOR2 complex. This binding event activates GATOR2, which then seeks out and inhibits the GATOR1 complex. Conversely, when amino acid levels are low, the Sestrin2 and CASTOR1 sensors remain inactive. This leaves GATOR1 free to perform its inhibitory role and halt cell growth.

Controlling the mTORC1 Growth Pathway

The ultimate target of the GATOR complex’s regulatory activity is a growth controller known as mTORC1 (mechanistic target of rapamycin complex 1). The GATOR system dictates whether mTORC1 is turned on or off. This control is exerted through a pair of proteins called the Rag GTPases. GATOR1 functions as a GTPase-Activating Protein, or GAP, for the Rag proteins, which means it is responsible for deactivating them.

When amino acid levels are low, the GATOR1 complex is active. In this state, it finds and inactivates the Rag proteins by stimulating the hydrolysis of a molecule called GTP. Inactive Rag proteins are unable to recruit mTORC1 to the surface of the lysosome. Without being brought to the lysosome, mTORC1 cannot be activated, which stops cell growth and triggers energy-conserving processes like autophagy.

When amino acid levels are high, the sequence is reversed. GATOR2 becomes active and inhibits GATOR1, leaving the Rag proteins in their active, GTP-bound state. These active Rag proteins then recruit mTORC1 to the lysosomal surface. Here, mTORC1 is switched on, launching a cascade of signals that drive protein synthesis, lipid production, and overall cell proliferation.

Involvement in Human Health and Disease

The control exerted by the GATOR complex is important for the health of the entire organism. When this system malfunctions, it can lead to serious diseases. Genetic mutations affecting the components of the GATOR complex, particularly the GATOR1 “brake” proteins like DEPDC5, have been directly linked to several human health conditions.

A primary consequence of losing GATOR1 function is that the mTORC1 pathway becomes constitutively active, meaning it is always turned on, regardless of amino acid levels. This leads to uncontrolled and inappropriate cell growth and proliferation. This hyperactivity of mTORC1 is the underlying cause of the associated pathologies.

This constant activation is directly linked to specific medical conditions. For example, mutations in GATOR1 components are a known cause of certain forms of drug-resistant epilepsy and related brain malformations, such as focal cortical dysplasia. Because uncontrolled cell growth is a defining feature of cancer, the GATOR complex and its regulation of mTORC1 are of interest in cancer research, as mutations that disable the GATOR1 brake have been found in various tumors.