Search for directed genic interactions:  

MLST8 ➞ RPTOR (1 - 5 of 5)
PMID: 19117990
Distinct roles for mammalian target of rapamycin complexes in the fibroblast response to transforming growth factor-beta. 		mTORC2 promotes ... is required for ... not mTORC1 activation ...   (details)

MLST8 ➞ RPTOR

Type:  positive regulation
Is this interaction correct?
Yes
No

Comments
Cause:  mTORC2   (MAPKAP1   MLST8   RICTOR   MTOR )
Theme:  mTORC1   (MLST8   RPTOR   MTOR )

PMID: 19117990

Distinct roles for mammalian target of rapamycin complexes in the fibroblast response to transforming growth factor-beta.
Source

Cancer research (1/1/2009)

Abstract

Distinct roles for mammalian target of rapamycin complexes in the fibroblast response to transforming growth factor-beta. Transforming growth factor-beta (TGF-beta) promotes a multitude of diverse biological processes, including growth arrest of epithelial cells and proliferation of fibroblasts. Although the TGF-beta signaling pathways that promote inhibition of epithelial cell growth are well characterized, less is known about the mechanisms mediating the positive response to this growth factor. Given that TGF-beta has been shown to promote fibrotic diseases and desmoplasia, identifying the fibroblast-specific TGF-beta signaling pathways is critical. Here, we investigate the role of mammalian target of rapamycin (mTOR), a known effector of phosphatidylinositol 3-kinase (PI3K) and promoter of cell growth, in the fibroblast response to TGF-beta. We show that TGF-beta activates mTOR complex 1 (mTORC1) in fibroblasts but not epithelial cells via a PI3K-Akt-TSC2-dependent pathway. Rapamycin, the pharmacologic inhibitor of mTOR, prevents TGF-beta-mediated anchorage-independent growth without affecting TGF-beta transcriptional responses or extracellular matrix protein induction. In addition to mTORC1, we also examined the role of mTORC2 in TGF-beta action. mTORC2 promotes TGF-beta-induced morphologic transformation and is required for TGF-beta-induced Akt S473 phosphorylation but not mTORC1 activation. Interestingly, both mTOR complexes are necessary for TGF-beta-mediated growth in soft agar. These results define distinct and overlapping roles for mTORC1 and mTORC2 in the fibroblast response to TGF-beta and suggest that inhibitors of mTOR signaling may be useful in treating fibrotic processes, such as desmoplasia.

PMID: 19864431
Regulation of mTOR complex 1 (mTORC1) by raptor Ser863 and multisite phosphorylation. 		... that mTORC1 activation leads to raptor multisite ...   (details)

MLST8 ➞ RPTOR

Type:  positive regulation
Is this interaction correct?
Yes
No

Comments
Cause:  mTORC1   (MLST8   RPTOR   MTOR )

PMID: 19864431

Regulation of mTOR complex 1 (mTORC1) by raptor Ser863 and multisite phosphorylation.
Source

The Journal of biological chemistry (1/1/2010)

Abstract

Regulation of mTOR complex 1 (mTORC1) by raptor Ser863 and multisite phosphorylation. The rapamycin-sensitive mTOR complex 1 (mTORC1) promotes protein synthesis, cell growth, and cell proliferation in response to growth factors and nutritional cues. To elucidate the poorly defined mechanisms underlying mTORC1 regulation, we have studied the phosphorylation of raptor, an mTOR-interacting partner. We have identified six raptor phosphorylation sites that lie in two centrally localized clusters (cluster 1, Ser (696) /Thr (706) and cluster 2, Ser (855) /Ser (859) /Ser (863) /Ser (877)) using tandem mass spectrometry and generated phosphospecific antibodies for each of these sites. Here we focus primarily although not exclusively on raptor Ser (863) phosphorylation. We report that insulin promotes mTORC1-associated phosphorylation of raptor Ser (863) via the canonical PI3K/TSC/Rheb pathway in a rapamycin-sensitive manner. mTORC1 activation by other stimuli (e.g. amino acids, epidermal growth factor/MAPK signaling, and cellular energy) also promote raptor Ser (863) phosphorylation. Rheb overexpression increases phosphorylation on raptor Ser (863) as well as on the five other identified sites (e.g. Ser (859), Ser (855), Ser (877), Ser (696), and Thr (706)). Strikingly, raptor Ser (863) phosphorylation is absolutely required for raptor Ser (859) and Ser (855) phosphorylation. These data suggest that mTORC1 activation leads to raptor multisite phosphorylation and that raptor Ser (863) phosphorylation functions as a master biochemical switch that modulates hierarchical raptor phosphorylation (e.g. on Ser (859) and Ser (855)). Importantly, mTORC1 containing phosphorylation site-defective raptor exhibits reduced in vitro kinase activity toward the substrate 4EBP1, with a multisite raptor 6A mutant more strongly defective that single-site raptor S863A. Taken together, these data suggest that complex raptor phosphorylation functions as a biochemical rheostat that modulates mTORC1 signaling in accordance with environmental cues.

PMID: 21307646
Mammalian target of rapamycin: hitting the bull's-eye for neurological disorders. 		... of mTOR signaling is mediated primarily... mTORC1 and ...   (details)

MLST8 ➞ RPTOR

Type:  positive regulation
Is this interaction correct?
Yes
No

Comments
Cause:  mTORC1   (MLST8   RPTOR   MTOR )
Theme:  mTOR-signaling   (RPTOR   MTOR )

PMID: 21307646

Mammalian target of rapamycin: hitting the bull's-eye for neurological disorders.
Source

Oxidative medicine and cellular longevity (0)

Abstract

Mammalian target of rapamycin: hitting the bull's-eye for neurological disorders. The mammalian target of rapamycin (mTOR) and its associated cell signaling pathways have garnered significant attention for their roles in cell biology and oncology. Interestingly, the explosion of information in this field has linked mTOR to neurological diseases with promising initial studies. mTOR, a 289 kDa serine/threonine protein kinase, plays an important role in cell growth and proliferation and is activated through phosphorylation in response to growth factors, mitogens, and hormones. Growth factors, amino acids, cellular nutrients, and oxygen deficiency can down-regulate mTOR activity. The function of mTOR signaling is mediated primarily through two mTOR complexes: mTORC1 and mTORC2. mTORC1 initiates cap-dependent protein translation, a rate-limiting step of protein synthesis, through the phosphorylation of the targets eukaryotic initiation factor 4E-binding protein 1 (4EBP1) and p70 ribosomal S6 kinase (p70S6K). In contrast, mTORC2 regulates development of the cytoskeleton and also controls cell survival. Although closely tied to tumorigenesis, mTOR and the downstream signaling pathways are significantly involved in the central nervous system (CNS) with synaptic plasticity, memory retention, neuroendocrine regulation associated with food intake and puberty, and modulation of neuronal repair following injury. The signaling pathways of mTOR also are believed to be a significant component in a number of neurological diseases, such as Alzheimer's disease, Parkinson's disease, and Huntington's disease, tuberous sclerosis, neurofibromatosis, fragile X syndrome, epilepsy, traumatic brain injury, and ischemic stroke. Here we describe the role of mTOR in the CNS and illustrate the potential for new strategies directed against neurological disorders.

PMID: 22425248
Transcription factor Foxo1 represses T-bet-mediated effector functions and promotes memory CD8(+) T cell differentiation. 		... of mTORC1 abrogated mTORC2-mediated Akt ...   (details)

MLST8 ➞ RPTOR

Type:  positive regulation
Is this interaction correct?
Yes
No

Comments
Cause:  mTORC2   (MAPKAP1   MLST8   RICTOR   MTOR )
Theme:  mTORC1   (MLST8   RPTOR   MTOR )

PMID: 22425248

Transcription factor Foxo1 represses T-bet-mediated effector functions and promotes memory CD8(+) T cell differentiation.
Source

Immunity (3/23/2012)

Abstract

Transcription factor Foxo1 represses T-bet-mediated effector functions and promotes memory CD8 (+) T cell differentiation. The evolutionary conserved Foxo transcription factors are important regulators of quiescence and longevity. Although, Foxo1 is known to be important in regulating CD8 (+) T cell trafficking and homeostasis, its role in functional differentiation of antigen-stimulated CD8 (+) T cells is unclear. Herein, we demonstrate that inactivation of Foxo1 was essential for instructing T-bet transcription factor-mediated effector differentiation of CD8 (+) T cells. The Foxo1 inactivation was dependent on mTORC1 kinase, given that blockade of mTORC1 abrogated mTORC2-mediated Akt (Ser473) kinase phosphorylation, resulting in Foxo1-dependent switch from T-bet to Eomesodermin transcription factor activation and increase in memory precursors. Silencing Foxo1 ablated interleukin-12- and rapamycin-enhanced CD8 (+) T cell memory responses and restored T-bet-mediated effector functions. These results demonstrate an essential role of Foxo1 in actively repressing effector or terminal differentiation processes to promote memory CD8 (+) T cell development and identify the functionally diverse mechanisms utilized by Foxo1 to promote quiescence and longevity.

PMID: 22980037
Shedding new light on neurodegenerative diseases through the mammalian target of rapamycin. 		mTOR signaling is dependent upon ... and mTORC2 complexes ...   (details)

MLST8 ➞ RPTOR

Type:  positive regulation
Is this interaction correct?
Yes
No

Comments
Cause:  mTORC2   (MAPKAP1   MLST8   RICTOR   MTOR )
Theme:  mTOR-signaling   (MLST8   RPTOR   MTOR )

PMID: 22980037

Shedding new light on neurodegenerative diseases through the mammalian target of rapamycin.
Source

Progress in neurobiology (November 2012)

Abstract

Shedding new light on neurodegenerative diseases through the mammalian target of rapamycin. Neurodegenerative disorders affect a significant portion of the world's population leading to either disability or death for almost 30 million individuals worldwide. One novel therapeutic target that may offer promise for multiple disease entities that involve Alzheimer's disease, Parkinson's disease, epilepsy, trauma, stroke, and tumors of the nervous system is the mammalian target of rapamycin (mTOR). mTOR signaling is dependent upon the mTORC1 and mTORC2 complexes that are composed of mTOR and several regulatory proteins including the tuberous sclerosis complex (TSC1, hamartin/TSC2, tuberin). Through a number of integrated cell signaling pathways that involve those of mTORC1 and mTORC2 as well as more novel signaling tied to cytokines, Wnt, and forkhead, mTOR can foster stem cellular proliferation, tissue repair and longevity, and synaptic growth by modulating mechanisms that foster both apoptosis and autophagy. Yet, mTOR through its proliferative capacity may sometimes be detrimental to central nervous system recovery and even promote tumorigenesis. Further knowledge of mTOR and the critical pathways governed by this serine/threonine protein kinase can bring new light for neurodegeneration and other related diseases that currently require new and robust treatments.