2 - The TSC1–TSC2 Complex: A Key Signal-Integrating Node Upstream of TOR
Section snippets
Abstract
The TSC1 (hamartin) and TSC2 (tuberin) proteins function as a heterodimer that integrates diverse extracellular and intracellular signals to regulate the two TOR complexes (TORC1 and TORC2; mTORC1 and mTORC2 in mammals) and the processes of cell growth and proliferation. The TSC1–TSC2 complex negatively regulates TORC1 through its GTPase-activating protein (GAP) activity toward the small G-protein Rheb (Ras homolog enriched in brain), an essential activator of TORC1. In contrast, TORC2 in
The TSC1–TSC2 Complex Negatively Regulates Growth and Proliferation
Since the genetic loss of TSC1 and TSC2 that underlies TSC results in tumor formation in multiple organs, these genes have long been classified as tumor suppressors. An important milestone in understanding the function of the TSC1–TSC2 complex came when its tumor suppressor activity was linked at the molecular level to the GAP domain of TSC2 30, 31 and to control over a basic physiological process—cell growth. Germline ablation of either Tsc1 or Tsc2 in rodents leads to embryonic lethality 32,
Upstream Regulation: The TSC1–TSC2 Complex Integrates Diverse Signals to Regulate mTORC1
As a critical upstream regulator of mTORC1, the TSC1–TSC2 complex has emerged as a signal-integrating hub that senses cell growth conditions. In general, conditions favorable to cell growth and proliferation inhibit the TSC1–TSC2 complex to activate Rheb and mTORC1, while poor growth conditions activate the TSC1–TSC2 complex to inhibit Rheb and mTORC1. Multisite phosphorylation of specific serine and threonine residues on TSC1 and TSC2 is the primary mechanism by which the complex senses these
Aberrant Inhibition of the TSC1–TSC2 Complex Leading to Activation of mTORC1 in the Majority of Human Tumors
The complexity and breadth of the signaling network upstream of the TSC1–TSC2 complex is a testament to the importance of proper regulation of mTORC1 in the tight control over cellular growth and proliferation. Aberrantly elevated mTORC1 signaling is detected in the majority of genetic tumor syndromes and sporadic cancers [132]. Several of the most commonly activated oncogene products and inactivated tumor suppressors lie upstream of the TSC1–TSC2 complex (Figure 2.6). Amplifications and
Important Outstanding Questions Concerning the TSC1–TSC2 Complex
The enormous increase in our understanding of the TSC1–TSC2 complex and upstream regulation of mTORC1 over the past decade raises several remaining fundamental questions. First, a comprehensive understanding of how phosphorylation regulates the complex needs to be developed. This should include determining the complete repertoire of kinases and pathways upstream of the complex, identifying all phosphorylation sites, and characterizing the hierarchy of the phosphorylation sites and how they
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