Therapeutic targets for cancer: current concepts with PI 3-K, Akt, & mTOR.
Year: 2013
Type: article
Abstract: Phosphoinositide 3-kinase (PI 3-K), protein kinase B (Akt), and the mammalian target of rapamycin (mTOR) significantly impact multiple biological functions that influence cellular development, survival, and demise1. Given the ability of these pathways to foster robust cellular proliferation, PI 3-K, Akt, and mTOR have become compelling targets for the treatment of tumourigenesis that can occur throughout the body. Receptor tyrosine kinase (RTK) and the G protein-coupled receptor (CPCR) are required for the activation of PI 3-K. Once active, PI 3-K phosphorylates membrane lipids and mediates the translocation of Akt from the cytosol to the plasma membrane by promoting the binding of Akt to PI-3,4-P2 and PI-3, 4, 5-P3 through the plectrin homology (PH) domain. Akt is subsequently activated through the phosphorylation of its residues serine473 and threonine308 by phosphoinositide dependent kinase (PDK) PDK1 and PDK2.
mTOR is a serine/threonine protein kinase (289 kDa protein) that is dependent upon the activation of the PI 3-K and Akt cascade. mTOR signaling also relies upon the protein complexes mTOR Complex 1 (mTORC1) or mTOR Complex 2 (mTORC2), each of which contains mTOR and a number of regulatory proteins. Phosphorylation of mTOR can occur at several locations. The C-terminal domain with sequence homology to the catalytic domain of the PI 3-K family contains several phosphorylation sites that regulate mTOR activity, including serine2448 that is a target of Akt2. Another regulatory component of mTORC1 linked to Akt involves the proline rich Akt substrate 40 kDa (PRAS40) that contains a consensus sequence (RXRXXS/T) for Akt. Akt phosphorylates threonine246 on PRAS40 and results in the dissociation of PRAS40 from mTORC13. This process leads to the binding of phosphorylated PRAS40 to protein 14-3-3 to inhibit PRAS40 and activate the mTOR pathway. Tuberous sclerosis complex (TSC) 1 (hamartin)/TSC2 (tuberin) complex also is a target for the modulation of mTORC1 activity. In the absence of Akt activity, the TSC1/TSC2 complex is a negative regulator of mTORC1. TSC2 functions as a GTPase-activating protein (GAP) that converts a small G protein Ras homologue enriched in brain (Rheb-GTP) to the inactive GDP-bound form (Rheb-GDP). The active form Rheb-GTP can result in mTORC1 activation. Akt phosphorylates TSC2 on multiple sites that leads to the destabilization of TSC2 and disruption of its interaction with TSC1. The phosphorylation of TSC2 on the residues of serine939, serine981, and threonine1462 can increase its binding to protein 14-3-3 and lead to cellular sequestration, disruption of the TSC1/TSC2 complex, and subsequent activation of Rheb and the mTOR pathway. In addition, Akt can promote the activation of mTORC1 and the mTOR pathway through I-kappaB kinase - α (IKKα). IKKα regulates mTOR activity by associating with Raptor, (regulatory-associated protein of mTOR), that is Akt dependent.
Source: Europe PMC (PubMed Central)
Author: Kenneth Maiese
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W2199927314