Table 1.

Regulation of mTOR by cAMP and cGMP signaling pathways.

No.	Reagents	Signaling Cascade and Effects	Mechanism	Targets	Readouts	Ref.
	Inhibition by cAMP
1	Forskolin, IBMX	Inhibits interleukin-2-dependent mTORC1 activation in IL-2-responsive lymphoid cells	Activates PKA and inhibits PI3K and S6K1 activation	PI3K	p-S6K1	[23]
2	Forskolin, cAMP analogue	Prevents the effect of insulin on mTORC1 activation in 3T3-L1 adipocyte	Inhibits mTOR phosphorylation and activation	mTOR	p-4E-BP	[24]
3	Forskolin, IBMX	Inhibits insulin and amino acid-stimulated mTORC1 activation in MEFs and HEK293 cells	Promotes mTOR complex disassembly and inhibits mTOR catalytic activity	mTOR	p-S6K1, p-4E-BP	[25]
4	Forskolin, IBMX	Inhibits serum-stimulated mTORC2 activation after prolonged cAMP elevation in MEFs and HEK293 cells	Promotes mTOR complex disassembly and inhibits mTOR catalytic activity	mTOR	p-PKB, p-PKC	[25]
5	Forskolin, cAMP analogue	Inhibits mTORC1 activation in Ret/PTC1-positive thyroid carcinoma cell TPC-1	Inhibits the Raf/ERK cascade and depends on PKA	Raf/ERK cascade	p-S6K1, p-4E-BP	[26]
6	cAMP analogue	Inhibits EGF-stimulated mTOR activity in Swiss 3T3, HEK293, COS, and Rat2 cells	Inhibits PI3K activity, PDK1 translocation to plasma membrane, and AKT phosphorylation	PI3K/PDK/AKT cascade	p-S6K1	[27]
7	Glucagon, cAMP analogue	Inhibits insulin- and amino acid-induced mTORC1 activation in serum-free primary rat hepatocytes	NA	NA	p-S6K1, p-4E-BP1	[28]
8	Glucagon	Represses both basal and amino acid-induced mTORC1 activation in perfused rat liver	Activates PKA and enhances phosphorylation of LKB1 Thr172 and AMPK Ser428	LKB1/AMPK pathway	p-S6K1, p-4E-BP1	[29]
9	Glucagon	Acts in a dominant manner to repress insulin-induced mTORC1 signaling in perfused rat liver	Reduces assembly of the mTORC1-eIF3 complex	mTORC1-eIF3 complex	p-S6K1, p-4E-BP1	[30]
10	PTH/PTHrP	Leads to mTORC1 inhibition during skeletal development	Inhibits SIK3 and prevents DEPTOR degradation	DEPTOR	p-S6K, p-S6	[31]
	Activation by cAMP
11	Forskolin, GLP-1RA exenatide	Activates mTORC1 in isolated rat islets	Mobilizes intracellular Ca2+ influx and upregulates ATP production	KATP channel	p-S6K1	[35]
12	Adrenalin, cAMP analogue	Potentiates insulin-stimulated mTORC1 activation in soleus muscles ex vivo	Depends on cAMP and Epac but not PKA	EPAC	p-S6K1	[36]
13	GLP-1, Forskolin	Leads to S6 phosphorylation in the pancreatic beta cell line MIN6 and islets	Depends on PKA phosphorylation of S6 at Ser235/Ser236	S6	p-S6	[37]
14	TSH	Activates mTORC1 in PC Cl3 rat thyroid cells	Acts in part via phosphorylation of PRAS40 Thr246 by PKA and augments 4E-BP1 binding to RAPTOR	PRAS40	p-S6K1, p-4E-BP1	[38]
15	hCG, Forskolin	Activates mTORC1 in theca-interstitial cells	Involved in cAMP-dependent activation of AKT	AKT	p-S6K, p-S6, p-4E-BP1	[39]
16	cAMP	Leads mTORC1 activation in HEK293 cells	Disrupts the interaction of PDE4D with RHEB and increases the interaction between RHEB and mTOR	PDE4D and RHEB	p-S6K1, p-4EBP1	[40]
17	β-AR agonist	Leads to mTORC1 activation in adipocyte and mouse adipose tissue	Direct PKA phosphorylation of RAPTOR Ser791 and mTOR Ser1276, Ser1288, and Ser2112	RAPTOR and mTOR	p-S6K1	[41]
18	GLP-1RA liraglutide	Promotes mTORC1 activation in CHO cells expressing GLP-1R	Direct PKA phosphorylation of RAPTOR Ser791	RAPTOR	p-S6K1	[62]
	Activation by cGMP
19	Natriuretic peptides	Leads to mTORC1 activation in adipocyte and mouse adipose tissue	Direct PKG phosphorylation of RAPTOR Ser791	RAPTOR	p-S6K, p-S6	[42]
	Inhibition by cGMP
20	PKG	Inhibits mTORC1 and promotes autophagy activity	Direct PKG1 phosphorylation of TSC2 Ser1365 and Ser1366, PKG1α C42 oxidation reduces TSC2 phosphorylation and amplifies mTORC1 activity	TSC2	p-S6K1, p-4E-BP1	[44,46]
	Indirect Regulation via p38
21	p38	Activates mTORC1 by inhibiting TSC2	Controls TSC2 Ser1210 phosphorylation through MAPKAPK2 (MK2) and increases 14-3-3 binding	TSC2	p-TSC2	[49]
22	p38β	Leads to TORC1 activation in stressed mammalian and Drosophila tissue culture	Occurs downstream of or in parallel to TSC2 and upstream of Rag activation	ND	p-S6K1, p-4E-BP1	[50]
23	p38	Leads to mTORC1 activation in reperfused heart and reoxygenated or H2O2-treated cardiomyocytes (NRVMs)	ROS downregulates REDD1 and promotes TSC2/14-3-3 association	TSC2	p-S6	[51]
24	p38γ/δ	Leads to mTORC1 activation in postnatal cardiac hypertrophic growth	Phosphorylates DEPTOR and leads to its degradation and mTOR activation	DEPTOR	p-mTOR, p-S6K1, p-S6	[52]
	Indirect Regulation via GSK3β
25	GSK3β	Phosphorylates TSC2 and results in mTORC1 inhibition	PKA physically associates with, phosphorylates, and inactivates both isoforms of GSK3	TSC2	p-AKT	[57,58]
26	GSK3β	Required for mTORC2 inhibition during ER stress	Phosphorylates RICTOR at Ser1235, interferes with the binding of AKT to mTORC2 and thus inhibits AKT	RICTOR	p-AKT	[59]
27	GSK3β	Required for mTORC2 inhibition	Directly phosphorylates RICTOR at Thr1695, recruits FBW7 and leads to RICTOR degradation	RICTOR	p-AKT, p-SGK1, p-PKCα	[60]
28	GSK3β	Required for mTORC2 activation in response to BDNF or insulin stimulation in cultured neurons and mouse brain	Increases prosurvival signaling	NA	p-S6, p-AKT	[61]

Abbreviations: IBMX: 3-Isobutyl-1-methylxanthine; MEFs: mouse embryonic fibroblast; PTH/PTHrP: parathyroid hormone/PTH-related peptide; GLP-1: glucagon-like peptide-1; GLP-1RA: GLP-1 receptor agonist; KATP channels: ATP-sensitive K+ channels; TSH: thyroid-stimulating hormone; hCG: human chorionic gonadotropin; β-AR: β-adrenergic receptor; NRVMs: neonatal rat ventricular myocytes; ER: endoplasmic reticulum; GPCRs: G protein-coupled receptors.