Insulin signalling to mTOR mediated by the Akt/PKB substrate PRAS40 (Nat Cell Biol, 2007, 9:316-323)

報告日期: 2007/11/27
報告時間: 15:10/16:00
報告學生: 徐宗溢
講評老師: 陳麗玉
附件下載:

http://basicmed.med.ncku.edu.tw/upload_data/961127-1.pdf

Insulin signaling to mTOR by the Akt/PKB substrate PRAS40

 

Speaker: Chung-Yi Hsu

Commentator: Lih-Yuh C. Wing

Date: November 27, 2007

 

Abstract

Insulin induces protein synthesis and cell growth through activation of protein kinase Akt and mammalian target of rapamycin (mTOR). mTOR is activated by a small GTP protein, ras homolog enriched in brain (Rheb), inhibited by tuberous sclerosis complex (TSC) 2. Akt activates mTOR through phosphorylation and inhibition of TSC2. mTOR interacts with raptor and G-protein b-subunit-like protein (GbL) to form mTORC1, a nutrient and insulin-regulated complex. The physiological requirement of Akt phosphorylation of TSC2 for mTOR activation is not clear. Kovacina et al., [1] isolated a new substrate of Akt, proline-rich Akt substrate of 40 kDa (PRAS40), in rat hepatoma cells in 2003. Level of phosphorylated PRAS40 is increased during melanoma tumor progression paralleling decreasing tumor cell apoptosis [2]. However, the function of PRAS40 is unknown. The author wants to explore properties of raptor, GbL and other unidentified mTOR-binding protein in order to provide clues to the mechanism underlying insulin-regulated mTOR activation. In this study, PRAS40 was identified as a novel mTOR-binding protein that mediates Akt signals to mTOR. The interaction between PRAS40 and mTOR is induced under conditions that inhibit mTOR, such as nutrient starvation and mitochondria metabolic inhibition. Binding of PRAS40 inhibits mTOR activity and suppresses constitutively activation of mTOR in cells lacking of TSC2. The phosphorylation of PRAS40 on threonine 246 induced by Akt and association with 14-3-3 are crucial for insulin-stimulated mTOR activation. These findings identify PRAS40 as an important regulator of Akt-mTOR pathway and a potential target for the treatment of cancers.

 

Reference

1.     Kovacina KS, Park GY, Bae SS, Guzzetta AW, Schaefer E, Birnbaum MJ, Roth RA. Identification of a proline-rich Akt substrate as a 14-3-3 binding partner. J Biol Chem 2003 21:10189-10194.

2.     Madhunapantula SV, Sharma A, Robertson GP. PRAS40 deregulates apoptosis in malignant melanoma. Cancer Res. 2007 15:3626-3636.