Rag GTPases–Mechanistic target of rapamycin complex 1 signaling complex (Rag–mTORC1 complex)

The Rag GTPases–Mechanistic target of rapamycin complex 1 (mTORC1) signaling complex is a multi-protein assembly that integrates nutrient availability with cellular growth [1, 3]. It consists of the mTORC1 kinase complex and the Rag family of small GTPases (RagA, RagB, RagC, and RagD), which function as obligate heterodimers [1, 10]. In the presence of amino acids, the active Rag heterodimer recruits mTORC1 to the lysosomal surface via the Ragulator scaffold [4, 7]. At the lysosome, mTORC1 is positioned for activation by the small GTPase Rheb, which responds to growth factor and energy signals [4, 5]. This complex acts as a master regulator of anabolic processes like protein and lipid synthesis while inhibiting catabolic processes such as autophagy [3, 13]. Dysregulation of this signaling axis, often through hyperactivation, is a hallmark of various diseases, including many types of cancer, metabolic disorders like diabetes and obesity, and neurodegenerative conditions [1, 6, 13]. Therapeutic strategies targeting this complex include allosteric mTORC1 inhibitors like rapamycin and its analogs (rapalogs), as well as newer ATP-competitive inhibitors [6, 9, 12]. Emerging research also focuses on small molecules that could potentially disrupt the Rag-mediated recruitment process to achieve more selective therapeutic effects [6, 8].

Other names

Rag-mTORC1 complexRag-mTORC1 axisRag-mTORC1 signaling machineAmino acid-sensing mTORC1 complexRag-mTORC1 pathway

Allosteric inhibition of mTORC1 (rapalogs) and competitive inhibition of the mTOR kinase domain (ATP-competitive inhibitors), leading to the suppression of nutrient-dependent growth signaling.