MTOR signaling pathway - Homo sapiens (human)

Curator(s): Peter D'Adamo

The mammalian target of rapamycin (mTOR) is an atypical serine/threonine kinase that is present in two distinct complexes. mTOR complex 1 (mTORC1) is composed of mTOR, Raptor, GβL (mLST8), and Deptor and is partially inhibited by rapamycin. mTORC1 integrates multiple signals reflecting the availability of growth factors, nutrients, or energy to promote either cellular growth when conditions are favorable or catabolic processes during stress or when conditions are unfavorable. Growth factors and hormones (e.g. insulin) signal to mTORC1 via Akt, which inactivates TSC2 to prevent inhibition of mTORC1. Alternatively, low ATP levels lead to the AMPK-dependent activation of TSC2 to reduce mTORC1 signaling. Amino acid availability is signaled to mTORC1 via a pathway involving the Rag proteins. Active mTORC1 has a number of downstream biological effects including translation of mRNA via the phosphorylation of downstream targets (4E-BP1 and p70 S6 Kinase), suppression of autophagy, ribosome biogenesis, and activation of transcription leading to mitochondrial metabolism or adipogenesis. The mTOR complex 2 (mTORC2) is composed of mTOR, Rictor, GβL, Sin1, PRR5/Protor-1, and Deptor and promotes cellular survival by activating Akt. mTORC2 also regulates cytoskeletal dynamics by activating PKCα and regulates ion transport and growth via SGK1 phosphorylation. Aberrant mTOR signaling is involved in many disease states including cancer, cardiovascular disease, and metabolic disorders.    
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MTOR signaling pathway - Homo sapiens (human) cluster_MTORC2 MTORC2 cluster_MTORC1 MTORC1 cluster_node34 WNT SIGNALING node1 2 node2 INS/IGF node2->node1 INS/IGF Insulin signaling pathways node2->Insulin signaling pathways MAPK Signaling Pathway node2->MAPK Signaling Pathway Ras/MAPK PI3K Insulin signaling pathways->PI3K node4 ERK1/2 MAPK Signaling Pathway->node4 node3 15 node4->node3 ERK1/2 node5 12 PI3K->node5 PI3K PIP3 PI3K->PIP3 pyruvate dehydrogenase kinase,isozyme 1 PDK1 AKT PDK1->AKT +p node6 29 AKT->node6 AKT node8 TSC1 TSC2 AKT->node8 +p PRAS40 AKT->PRAS40 MTOR1 AKT->MTOR1 node7 1 node8->node7 TSC1/TSC2 Ras homolog enriched in brain RHEB node8->RHEB node9 3 PIP3->PDK1 PIP3->node9 PIP3 REDD1 REDD1->node8 Hypoxia Hypoxia->REDD1 v-raf murine sarcoma viral oncogene homolog B1 BRAF RHEB->BRAF RHEB->MTOR1 node12 MTOR(2) RHEB->node12 cAMP AMPK cAMP->AMPK Metformin Metformin->AMPK AICAR AICAR->AMPK node10 16 AMPK->node8 +p AMPK->node10 AMPK AMPK->MTOR1 node11 20 node13 1 Differentiation BRAF->Differentiation node18 20 node19 1 Rapamycin Rapamycin->MTOR1 node20 10 hypoxia inducible factor 1,alpha subunit (basic helix-loop-helix transcription factor) HIF1A HIF1A->node20 HIF1A DNA HIF1A->DNA node21 S6K1/2 S6 node21->S6 +p node22 4EBP1 eukaryotic translation initiation factor 4E EIF4E node22->EIF4E +p ATG1 Autophagy regulation ATG1->Autophagy regulation VEGF DNA->VEGF node23 17 VEGF->node23 VEGF VEGF Signaling pathway VEGF->VEGF Signaling pathway Wortmannin Wortmannin->PI3K LY294002 LY294002->PI3K node24 LKB1 STRAD MO25 node24->AMPK +p Energy stress Energy stress->node24 Extracellular Amino Acids node25 ? Extracellular Amino Acids->node25 node32 Rag A/B Rag C/D Extracellular Amino Acids->node32 node25->node8 ? Growth factors Growth factors->node2 Hormones Hormones->node2 Translation S6->Translation node26 1 EIF4E->node26 EIF4E Cell growth Translation->Cell growth node27 1 PRAS40->node27 PRAS40 RAPTOR PRAS40->RAPTOR node28 2 node29 1 node30 2 node31 5 GSK3 GSK3->node8 GSK3->node31 GSK3 node32->RAPTOR Ribosome biogenesis node33 10 peroxisome proliferator-activated receptor gamma PPARG PPARG->node33 PPARG Adipogenesis PPARG->Adipogenesis MTOR1->node18 MTOR1 MTOR1->HIF1A +p MTOR1->node21 +p MTOR1->node22 MTOR1->ATG1 +p MTOR1->Ribosome biogenesis MTOR1->PPARG node17 DEPTOR(1) node17->MTOR1 DVL DVL->node30 DVL DVL->GSK3 FRIZZLED FRIZZLED->node29 FRIZZLED guanine nucleotide binding protein (G protein),q polypeptide GNAQ FRIZZLED->GNAQ GNAQ->DVL node16 GβL(1) node16->MTOR1 node12->AKT +p node12->node11 MTOR(2) node15 DEPTOR(2) node12->node15 node14 GβL(2) node12->node14 RPTOR independent companion of MTOR,complex 2 RICTOR node12->RICTOR RICTOR->node13 RICTOR RAPTOR->node19 RAPTOR RAPTOR->MTOR1 proline rich 5 (renal) PRR5 PRR5->RICTOR SIN1 SIN1->RICTOR WNT WNT->node28 WNT WNT->FRIZZLED print "