PRR5, a Novel Component of mTOR Complex 2, Regulates Platelet-derived Growth Factor Receptor β Expression and Signaling

Abstract

The protein kinase mammalian target of rapamycin (mTOR) plays an important role in the coordinate regulation of cellular responses to nutritional and growth factor conditions. mTOR achieves these roles through interacting with raptor and rictor to form two distinct protein complexes, mTORC1 and mTORC2. Previous studies have been focused on mTORC1 to elucidate the central roles of the complex in mediating nutritional and growth factor signals to the protein synthesis machinery. Cell growth relies on coordinated regulation of signaling pathways that integrate cellular physiological status in response to nutrient levels, growth factor signals, and environmental stress. Impairment of the coordinated regulation can lead to disastrous effects on cell physiology, resulting in cell death or uncontrolled growth. mTOR, 2 a member of the phosphatidylinositol kinase-related kinase family, has been known as a central player in the signaling pathway that regulates cell growth in response to a variety of cellular signals derived from nutrient levels, growth factors, and environmental stress (2-4). mTOR plays a central role in the signaling network that regulates a variety of cellular processes including ribosome biogenesis, protein synthesis, autophagy, and actin cytoskeleton organization; human diseases such as cancer, diabetes, obesity, and harmatoma syndrome are associated with defects in mTOR signaling (5-9).Recent years have seen discoveries of several mTOR effectors and binding proteins. mTOR exists in two multiprotein complexes, mTORC1 and mTORC2. mTORC1 consists of mTOR, raptor, G␤L, and PRAS40, and it functions to regulate protein synthesis and cell growth in response to nutrient levels and growth factor signals (10 -14). mTORC1 regulates phosphorylations of at least two regulators of protein synthesis, S6K1 and 4E-BP1, and mediates nutrient and insulin signals to the cell growth machinery (2, 15). mTORC1 is regulated by TSC-Rheb (tuberous sclerosis complex-Ras homolog-enriched in brain) signaling (16 -19). mTORC2 consists of mTOR, rictor, G␤L, and Sin1, and it does not likely bind rapamycin-FK506-binding protein 12 complex, which makes mTORC2 distinctive from mTORC1 (13,20,21). Saccharomyces cerevisiae TORC2 consists of TOR2, LST8, AVO1 (Sin1 ortholog), and AVO3 (rictor ortholog) and two other components, AVO2 and BIT61, whose homologues have not been identified in higher eukaryotes (13,22,23). Functions and regulatory mechanisms of mTORC2 remain largely unknown. Recent studies showed that mTORC2 regulates protein kinase C ␣ phosphorylation, actin cytoskeleton organization, and Akt phosphorylation at 21,24,25). Recognizing the complex relationship between mTOR, S6K1, and * This study was supported by the Tuberous Sclerosis Alliance, the Minnesota Medical Foundation, American Heart Association Grant 0655706Z, and National Institutes of Health Grant DK072004. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in acc...

mTOR Signaling in Growth, Metabolism, and Disease

“…In addition, a crystal structure of the mTOR kinase domain bound to mLST8 showed that the rapamycin-FKBP12 complex binds to the FRB domain of mTOR to narrow the catalytic cleft and partially occlude substrates from the active site (Yang et al, 2013). Jacinto et al 2006;Yang et al 2006) and Protor1/2 (Pearce et al 2007;Thedieck et al 2007;Woo et al, 2007). Although rapamycin-FKBP12 complexes do not directly bind or inhibit mTORC2, prolonged rapamycin treatment does abrogate mTORC2 signaling, likely due to the inability of rapamycin-bound mTOR to incorporate into new mTORC2 complexes .…”

MHC class I and integrin ligation induce ERK activation via an mTORC2-dependent pathway

“…mTORC2 is composed of mTOR binding to rapamycin insensitive companion of mTOR (Rictor), GβL, stress-activated protein kinase-interacting protein 1 (Sin1) and the newly discovered associations with PRoline-Rich protein 5 (PRR5) or the synonymous protein observed with Rictor 1 (Protor-1), and P-REX1 [8][9][10][11][12]. mTORC2 activates Akt at Ser473, Rac GTPase, cell migration and effects reorganization of the actin cytoskeleton [11][12][13][14]. Recent work utilizing mouse knockout models emphasizes the importance of mTOR for growth and proliferation in development [15,16].…”

“…mTORC1 phosphorylates p70 S6 Kinase and eukaryotic initiation factor 4E binding protein 1 which activate translational machinery to increase cell proliferation [6,7]. mTORC2 is composed of mTOR binding to rapamycin insensitive companion of mTOR (Rictor), GβL, stress-activated protein kinase-interacting protein 1 (Sin1) and the newly discovered associations with PRoline-Rich protein 5 (PRR5) or the synonymous protein observed with Rictor 1 (Protor-1), and P-REX1 [8][9][10][11][12]. mTORC2 activates Akt at Ser473, Rac GTPase, cell migration and effects reorganization of the actin cytoskeleton [11][12][13][14].…”

Evaluation of DNA polymorphism among cultivated and wild grapevine accessions from Azerbaijan

“…Resveratrol (3, 5, 4'-trihydroxystilbene) is a stilbene phytoalexin and a natural component of grape plant tissues (Woo et al 2007). Resveratrol has been found to inhibit the proliferation of a variety of human cancer cell lines, including those from breast, prostate, stomach, colon, pancreatic, and thyroid cancers when added to cells cultured outside the body.…”