Gene interactions and pathways from curated databases and text-mining

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Pathways - manually collected, often from reviews:

Protein-Protein interactions - manually collected from original source literature:

Studies that report less than 10 interactions are marked with *

Text-mined interactions from Literome

Inoki et al., Genes Dev 2003 : Rheb stimulates the phosphorylation of mTOR and plays an essential role in regulation of S6K and 4EBP1 in response to nutrients and cellular energy status
Kwiatkowski et al., Cancer Biol Ther 2003 (Tuberous Sclerosis) : Biochemical studies have shown that activated Akt phosphorylates TSC2 in the TSC1/TSC2 protein complex, inactivating it ; while TSC1/TSC2 has GAP activity for the Rheb GTPase ( a member of the ras family ), and activated Rheb-GTP activates mTOR
Kimball et al., Curr Opin Clin Nutr Metab Care 2004 : Tuberous sclerosis complex protein 2 is a GTPase activator protein for Rheb that is inhibited by amino acids, allowing Rheb to activate mTOR through a mechanism still to be delineated
Roccio et al., Oncogene 2006 : TSC2 is a GTPase activating protein for the small GTPase Ras homologue enriched in brain (Rheb) , GTP loading of which activates mTOR by a yet unidentified mechanism
Kwiatkowski et al., Hum Mol Genet 2005 (Hamartoma...) : In the absence of either TSC1 or TSC2, high levels of Rheb-GTP lead to constitutive activation of mTOR-raptor signaling, thereby leading to enhanced and deregulated protein synthesis and cell growth
Yang et al., Proc Natl Acad Sci U S A 2006 : We also observed that Rheb does not activate TORC2 in human embryonic kidney 293 cells, although it potently stimulates TORC1
Hanrahan et al., Methods Enzymol 2006 : Rheb activation of mTOR and S6K1 signaling
Karbowniczek et al., J Biol Chem 2006 : Importantly, the impact of Rheb on B-Raf/C-Raf heterodimerization and kinase activity are rapamycin-insensitive, indicating that they are independent of Rheb activation of the mammalian target of rapamycin-Raptor complex
Land et al., J Biol Chem 2007 (Neoplasms...) : Our work shows that activation of mTOR by Ras homologue enriched in brain (Rheb) overexpression potently enhances the activity of HIF1alpha and vascular endothelial growth factor ( VEGF ) -A secretion during hypoxia, which is reversed with rapamycin
Yoon et al., J Biol Chem 2007 (Breast Neoplasms) : In addition, the activation of mTOR by the overexpression of RHEB in MDA-MB-231 cells increased the synthetic rates of both FASN and ACCalpha
Karbowniczek et al., J Invest Dermatol 2008 (Melanoma...) : mTOR is directly activated by the small guanosine triphosphatase Ras homolog enriched in brain (Rheb) , in a farnesylation dependent manner
Li et al., J Biol Chem 2007 : Rheb , a Ras related small GTPase, is a key upstream activator of mTOR
Bai et al., Science 2007 : Rheb activates mTOR by antagonizing its endogenous inhibitor, FKBP38 ... We show that Rheb regulates mTOR through FKBP38, a member of the FK506 binding protein ( FKBP ) family that is structurally related to FKBP12 ... Rheb interacts directly with FKBP38 and prevents its association with mTOR in a guanosine 5'-triphosphate ( GTP ) -dependent manner
Sato et al., Methods Enzymol 2008 : Rheb plays critical roles in the activation of mTOR , a serine/threonine kinase that is involved in the activation of protein synthesis and growth
Schewe et al., Proc Natl Acad Sci U S A 2008 (Carcinoma, Squamous Cell...) : Downstream, ATF6alpha induces survival through the up-regulation of Rheb and activation of mTOR signaling independent of Akt
Chakrabarti et al., Mol Endocrinol 2008 : The activity of mTORC1 in 3T3-L1 adipocytes was up-regulated by stable expression of either constitutively active Rheb or dominant negative AMP activated protein kinase
Ma et al., J Biol Chem 2008 : The Ras-like small GTPase Rheb is an upstream activator of the mammalian target of rapamycin (mTOR)
Wang et al., J Mol Cell Cardiol 2008 (Cardiomegaly) : Ras homolog enriched in brain (Rheb) positively regulates mTORC1 ... We have studied whether Rheb is sufficient to activate mTOR signaling and promote protein synthesis and cardiac hypertrophy in adult rat ventricular cardiomyocytes ( ARVC ) ... Overexpression of Rheb in ARVC activated mTORC1 signaling, several components of the translational machinery and stimulated protein synthesis
Avruch et al., Am J Physiol Endocrinol Metab 2009 : The rag heterodimer interacts directly with mTORC1 and may direct mTORC1 to the Rheb containing vesicular compartment in response to amino acid sufficiency, enabling Rheb-GTP activation of mTORC1
Codeluppi et al., J Neurosci 2009 (Disease Models, Animal...) : Indeed, we found that Rheb is required for EGF dependent mTOR activation in spinal cord astrocytes, whereas the Ras-MAP kinase pathway does not appear to be involved ... Furthermore, increased Rheb expression likely contributes to mTOR activation in the injured spinal cord
Uhlenbrock et al., FEBS Lett 2009 : Recent studies document that Rheb activates mTORC1 via direct, GTP dependent interaction with the peptidyl-prolyl-cis/trans-isomerase FKBP38, which is proposed to act as an inhibitor of mTORC1
Dunlop et al., Cell Signal 2009 : Finally, we show that activation of mTORC1 by both Rheb and RhebL1 is impaired by FKBP38
Gao et al., Biol Reprod 2009 : The abundance of FRAP1 , RAPTOR, RICTOR, TSC1, and TSC2 mRNAs in endometria was unaffected by pregnancy status or by day of the estrous cycle or pregnancy ; however, levels of LST8, MAPKAP1, RHEB , and EIF4EBP1 mRNA increased in endometria during early pregnancy
Sato et al., J Biol Chem 2009 : The activation of mTORC1 by Rheb can be faithfully reproduced in vitro by using mTORC1 immunoprecipitated by the use of anti-raptor antibody from mammalian cells starved for nutrients ... FKBP38, a recently proposed mediator of Rheb action, appears not to be involved in the Rheb dependent activation of mTORC1 in vitro, because the preparation of mTORC1 that is devoid of FKBP38 is still activated by Rheb ... PRAS40, a TOR signaling ( TOS ) motif containing protein that competes with the binding of 4EBP1 to mTORC1, inhibits Rheb induced activation of mTORC1
Acosta-Jaquez et al., Mol Cell Biol 2009 : Here we focus on mTORC1 and show that TSC/Rheb signaling promotes mTOR S1261 phosphorylation in an amino acid dependent, rapamycin-insensitive, and autophosphorylation independent manner
Ma et al., J Biol Chem 2010 : The inhibitory action of FKBP38 is antagonized by Rheb , an oncogenic small GTPase, which interacts with FKBP38 and prevents its association with mTOR
Nie et al., Nat Neurosci 2010 : Furthermore, Tsc2 deficiency and hyperactive Rheb constitutively activated mTOR and inhibited ephrin induced growth cone collapse
Chakrabarti et al., Diabetes 2010 : Activation of mTORC1 signaling in 3T3-L1 adipocytes by ectopic expression of Rheb inhibits expression of ATGL and HSL at the level of transcription, suppresses lipolysis, increases de novo lipogenesis, and promotes intracellular accumulation of triglycerides
Vega-Rubin-de-Celis et al., Biochemistry 2010 : mTORC1 is regulated by the small GTPase Rheb , which in turn is regulated by the GTPase activating protein complex, TSC1/TSC2
Wagner et al., Am J Physiol Cell Physiol 2010 : Rheb overexpression induced mTORC1 activity and repressed contractile protein expression, but a farnesylation-deficient mutant ( C18S ) elicited the opposite effect
Lu et al., Cancer Res 2010 (Skin Neoplasms) : Small GTPase Ras homologue enriched in brain (RHEB) binds and activates the key metabolic regulator mTORC1 , which has an important role in cancer cells, but the role of RHEB in cancer pathogenesis has not been shown
Li et al., J Biol Chem 2010 : Similarly, active Rab5 selectively inhibits mTORC1 activation by Rag GTPases, which are involved in amino acid signaling, but does not inhibit the effect of Rheb , which directly binds and activates mTORC1
Goodman et al., Mol Biol Cell 2010 (Hypertrophy) : In this study, we determined that, in skeletal muscle, overexpression of Rheb stimulates a PI3K/PKB independent activation of mTOR signaling , and this is sufficient for the induction of a rapamycin-sensitive hypertrophic response
Lacher et al., Oncogene 2010 (Cell Transformation, Neoplastic...) : TSC2 negatively regulates the activity of the GTPase Rheb and thereby inhibits mammalian target of rapamycin complex 1 ( mTORC1 ) signaling
Dennis et al., J Biol Chem 2011 : In deprived cells, mTORC1 was activated by expressing either constitutively active ( ca ) Rheb or a caRagB·caRagC complex, and coexpression of the constructs had an additive effect
Zheng et al., Nat Cell Biol 2011 : Phosphorylation of Rheb at Ser 130 by PRAK impairs the nucleotide binding ability of Rheb and inhibits Rheb mediated mTORC1 activation
Wu et al., J Biol Chem 2011 : The p38ß-PRAK cascade targets Rheb to inhibit mTORC1 activity upon glucose depletion
Rapley et al., J Biol Chem 2011 : Furthermore, Rheb overexpression in 293E activated mTORC1 signaling completely without causing PRAS40 release ... In conclusion, dissociation of PRAS40 from mTORC1 and enhanced mTORC1 substrate binding results from Akt and mTORC1 activation and makes little or no contribution to mTORC1 signaling, which rather is determined by Rheb activation of mTOR catalytic activity, through mechanisms that remain to be fully elucidated
Sciarretta et al., Circulation 2012 (Metabolic Syndrome X...) : Rheb inhibition causes mTORC1 inhibition, because forced activation of Rheb, through Rheb overexpression in vitro and through inducible cardiac-specific Rheb overexpression in vivo, restored mTORC1 activity
Wu et al., J Biol Chem 2012 : Although expression of the Raptor T908A mutant did not affect the mTORC1 integrity, it markedly impaired the mTORC1 activation by insulin or by overexpression of the small GTP binding protein RheB under nutrient starvation
Hong-Brown et al., Am J Physiol Cell Physiol 2012 : Rag GTPases and AMPK/TSC2/Rheb mediate the differential regulation of mTORC1 signaling in response to alcohol and leucine
Xiao et al., PloS one 2012 (Breast Neoplasms) : BITC treatment decreased phosphorylation of mTOR and its downstream targets ( P70s6k and 4E-BP1 ) in cultured MDA-MB-231 and MCF-7 cells and MDA-MB-231 xenografts, but activation of mTOR by transient overexpression of its positive regulator Rheb failed to confer protection against BITC induced autophagy
Ögmundsdóttir et al., PloS one 2012 : Mammalian Target of Rapamycin Complex 1 ( mTORC1 ) is activated by growth factor regulated phosphoinositide 3-kinase (PI3K)/Akt/Rheb signalling and extracellular amino acids ( AAs ) to promote growth and proliferation
Li et al., J Biol Chem 2013 : Interestingly, MARK4 selectively inhibits mTORC1 activation by Rag GTPases, which are involved in amino acid signaling, but does not inhibit the effect of Rheb , which directly binds to and activates mTORC1
Ching et al., Hum Mol Genet 2013 (Myositis, Inclusion Body) : Expression of a constitutively active Rheb enhanced mTOR activity and increased the fiber size in VCP-IBM mouse skeletal muscle
Tamai et al., J Biol Chem 2013 (Hypertrophy) : Thus, Rheb dependent mTORC1 activation becomes essential for cardiomyocyte hypertrophic growth after early postnatal period