MTOR Signaling: Emerging Role of Cyclic Nucleotide-Dependent Protein Kinases and Implications for Cardiometabolic Disease

mTOR signaling network and cyclic nucleotide-dependent protein kinase pathway. Insulin acts through the PI3K pathway and leads to signaling cascades that further activate mTORC1 and mTORC2. Upstream regulators converge at the TSC complex to either activate or inhibit mTORC1 activity. The RAG GTPases are the key component of the amino acid sensing machinery. The second messenger signaling including cAMP and cGMP pathways regulates mTOR activity through both direct and indirect mechanisms. Abbreviations: mTOR: mechanistic target of rapamycin; RAPTOR: regulatory-associated protein of mTOR; RICTOR: rapamycin-insensitive companion of mTOR; DEPTOR: DEP domain-containing mTOR-interacting protein; mLST8: mammalian lethal with SEC13 protein 8; PRAS40: proline-rich AKT substrate of 40 kDa; mSIN1: mammalian stress-activated protein kinase-interaction protein 1; PROTOR: protein observed with RICTOR; TSC1/2: tuberous sclerosis complex 1/2; RHEB: Ras homolog mTORC1 binding; RAGs: Ras-related GTPases; IRS: insulin receptor substrate; PI3K: phosphoinositide 3-kinase; PIP3: phosphatidylinositol 3,4,5-triphosphate; PTEN: phosphatase and tensin homolog; PDK1: phosphoinositide-dependent protein kinase 1; GRB10: growth factor receptor bound protein 10; AKT: protein kinase B; ERK: extracellular signal-regulated kinase; RSK: ribosomal S6 kinase 1; TNF: tumor necrosis factor; IKKβ: inhibitor of nuclear factor kappa-B kinase subunit beta; AMPK: AMP-activated protein kinase; WNT: wingless and lnt-1; GSKβ: glycogen synthase kinase 3β; REDD1: regulated in development and DNA damage responses 1; p38 MAPK: p38 mitogen-activated protein kinases; MK2: MAPK activated protein kinase 2; ROS: reactive oxygen species; NO: nitric oxide; ANP: atrial natriuretic peptide; BNP: B-type natriuretic peptide; GPCR: G protein-coupled receptor; GC: guanylyl cyclase: sGC: soluble guanylyl cyclase; cAMP: cyclic adenosine monophosphate; cGMP: cyclic guanosine monophosphate; PKA: cAMP-dependent protein kinase; PKG: cGMP-dependent protein kinase; SIK3: salt-inducible kinase 3; PDEs: phosphodiesterases.

Publication

Regulation of mTOR Signaling: Emerging Role of Cyclic Nucleotide-Dependent Protein Kinases and Implications for Cardiometabolic Disease. (2023) Fubiao Shi, et al. Int J Mol Sci. 2023 Jul;24(14):11497. Figure: F1. All organisms Drosophila melanogaster Homo sapiens

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