Cell cycle control by the insulin-like growth factor signal: at the crossroad between cell growth and mitotic regulation

Figures & data

Table 1. Mode of action of the insulin/IGF ligands.

Physiology Pathology (Cancer)

* As suggested by scientific cumulative translational and clinical research and reviewed in [29] under growth/proliferative physio-pathological conditions in mammalians*

Figure 1. Growth/proliferative-related effects of the Insulin/IGF ligands/receptor system in mammalians*. *ased on predominant effects observed in isolated/optimized ex-vivo models or net clinical study end-point.

Table 2. Effects of constitutive gene KO for the insulin/IGF-receptors signal components on body/organ size.

Protein (gene)KO/Silencing	Species/models	Bodysize	Effect of gene ablation	References
IGF-I (igf1)	Mouse, drosophila	✓	Decrease	[320,321]
IGF-II (igf2)	Mouse, drosophila	✓	Decrease	[52,320,321]
IGF-IR (igf1r)	Mouse, drosophila	✓	Decrease	[320,322]
IR (insr)	Mouse, drosophila	✓	Decrease	[323,324]
M6PR(igf2r)	mouse	✓	Overgrowth	[70]
IRS-1 (irs1)	Mouse, drosophila	✓	Decrease	[99, 325, 326]
IRS-2 (irs2)	Mouse, drosophila	✓	Decrease	[326]
H/N/K Ras	Mouse	✓	Normal for H/N Ras KOdelayed embryo growth for KRas	[327]
PIK3C1A	Drosophila, mouse	✓	Decrease	[133]
PDK1	Mouse	✓	Decrease	[328–330]
AKT1/2/3	Mouse, drosophila	✓	Decrease	[147,331]
PTEN	Mammalian cells,drosophila	✓n.a*	Cell/tissue-specific overgrowth	[161,164,332]
TSC1/TSC2	Mouse, drosophila	✓	Overgrowth	[166,333]
mTORC1(h-raptor,dTOR)	Mouse cells and tissues,drosophila	n.a*✓	Decrease	[166]
mTORC2 (rictor)	Mouse cells and tissues	n.a*	Decrease	[215,334,335]
GSK3β	Mouse cells and tissues	n.a*	Perilethal;GSK3b KORescued pancreatic growth defectcaused by IR-/-	[204,205]
4EBP	Mouse	✓	Overgrowth not observed due to increased protein metabolism	[185,336]
S6K1	Mouse, drosophila	✓	Decrease	[279,337]
FOXO1/3α	Mouse, drosophila	✓	Foxo1-/- mice die perinatallyFoxo3a KO does not cause overgrowth	[320,321]

Figure 2. The essential circuitry for the Insulin/IGFs system involved in growth and proliferation signal (refer to text and Table IV).

Table 3. Summary of insulin/IGF signal transducers acting as oncogenic factors versus tumor suppressors.

Oncogenic	Tumor-suppressing
IGF-I/IGF-II*	M6PR/Igfr
IGF-1 R	PTEN
IR-A	GSK3β
PIK3CA(p110)	4EBP
PDK	TSC1 (Hamartin)
AKT	TSC2 (Tuberin)
RAS	FOXO
RAF	P21CIP
CyclinD1/D2	P27kip

*Only IGF-II has been confirmed to be broadly overexpressed in cancer [29]

Figure 3. Essential IGF ligands/receptor signal determinants for cell size net effect (refer to text for further explanation).

Table 4. Downstream signal targets and relevant PTM sites for the insulin/IGF signal transduction components implicated in cell growth and cell-cycle control.(a) www.phosphositeplus.com DB, (b) UniProt, [301].

	Signaling component/transducer	Y/S/T/K PTM residuesModulated by Ins/IGF*	Downstream direct targetsInvolved in growth/proliferation
	Insulin	n/a	Insulin receptor (InsR)
	Insulin Receptor and isoform A (InsR-A)	Y989, Y999,Y1101, Y1139, Y1185, Y1189/90, S1132/33, S1354, Y1351, Y1355, Y1361, T1375	IRS1, IRS2, (IRS3), IRS4
	IGF-I	n/a	IGF1R > Hybrid InsR/IGF1R ≫ InsR
	IGF-II	n/a	InsR-A = IGF1R > Hybrid InsR/IGF1R
	IGF-I receptor (IGF-IR)	Y974, Y981, Y988, K1055, Y1127, K1130, Y1161, Y1253, Y1281, Y1283, S1310/11/12, Y1346, Y1352	IRS1, IRS2, IRS4
	IRS-1	S24, Y47, Y107, S270, S303, S307, S312, S323, S330, S348, S362, T446, Y460, T495, S527, S531, Y546, Y608, S616, S629, S632, S639, Y658, Y760, Y891, Y935, Y1006, S1078, S1100/1101, S1142/45, Y1220	P85PI3K, GRB2, GRB10, SHC, UBF
	IRS-2	Y136, Y191, Y214, S306, S365, S577, Y628, Y649, Y671, Y734, Y758, Y814, Y911, Y970, Y1061, S1149, Y1242, Y1303	P85PI3K, GRB2, GRB10, SHC, 14.3.3, UBF, APC
	Shc1^p52	Y427	SOS1/2
	Grb2Grb10Grb14	GRB2: (Y209)GRB10: Y67, S150, S428 S476GRB14: S366	Grb2: Sos1Grb10: IR, IGF1RGrb14: chfr
	PIK3R1 (PI3Kp85)	S608	PIK3CA Type I class (p110 isoforms)
	PIK3CA (PI3K110α)	TBD	AKT1/2/3,
	PDK1	Y9, S25, S64, S241, T354, Y373, Y376, S394, S396/98, T513	AKT^S308, PKC, S6K, RSK, SGK
	PKB/AKT-1/2/3	AKT1:S129,Y176, K276sm, S308, T450, S473, S477, T479AKT2: S126, S131, T309,T451,S474,AKT3: T305, S472	S6K1/2, GSK3a/b, mSIN1^T89(mTORC2)TSC2, FOXO1/3a
	PKC-α,β,δ,β,ζ	PKCa: T638PKCb: TBDPKCd: T507, S645, S664PKCg: TBDPKCz: T410	S6K1, mTORC1/2?, c-Fos,Negative feedback target:IRS1
	PTEN	Y27, Y174, S380	PIP3 dephosphorylation (PI3K)
	RAS (H, K, N)	HRAS: Y32, T144, T148KRAS: Y32, Y64	Raf, PI3KCA, PKC, mTORC2
	B-Raf	S365, S429, S446	MEK1/2
	MEK1/2	MEK1: S218, S222MEK2: S222, S226	ERK1/2
	ERK1/2	ERK1: T202, Y204, Y210ERK2: T185, Y187	RSK1, TSC2, mTORC2, cFOS, cJUN, ETS1/2, ELK1, egr-1, Cyclin D1Negative feedback direct targets:MEK1, RAF, SOS1, IRS2
	RSK1/2	RSK1: S221, T573, T359, S380RSK2: S19, T577	GSK3, S6K1^S235/236, c-FOS, p27KIP1, TP53Negative feedback direct target:SOS1
	S6K1/S6K2	S6K1: T252, S394, T412, S427, S434, T444, S447, K516acS6K2: T228, S473	GSK3β, eIF3, Ribosomal biogenesis nucleolar proteins (Nop56, Nop14, Gar1, Rrp9, Rrp12, Rrp15, Pwp2)Negative feedback targets:IRS1, mTORC2^S1135
	4EBP1	T37, T41, S44, T46, S65, T68, T70, S101, S112	eIF4E, p21^CIP1, p27^KIP1
	GSK3β	S9, T43, Y216	CyclinD1, 4EBP1Negative feedback targets:HRAS, PTEN
	TSC1TSC2	TSC1: not directly targetedTSC2: S939, S981, S1387, S1452, T1462	TSC1: TSC2, Rheb1, PRAS40, p27^KIP1TSC2: TSC1, p27^KIP1, CyclinB1
	RHEB1	S130	mTORC1
	mTORC1:mTORRaptorLST8Deptor	mTOR: S1261, S1415, T2446, S2448, S2481Raptor: S696, S722, S855, S859, S863, T865, S877, S881/82, T883, S884, S886/87, T889LST8: TBDDeptor:, T241, S244, S258, T259, S263, S265, S282/83, S286/87, S291, S293, T297/98/99	S6K1^S389,S235/236,S240/244, 4EBP1^S37/46, TIF1A/RRN3Negative feedback target:IRS1, mTORC2 (via S6K1)
	mTORC2:mTORRictorLST8SIN1	mTOR: see aboveRICTOR: T1135, S1177LST8: TBDSIN1: T86, S128	AKT^S473, RSK^S380,E2F->cMyc (transcription)Upstream positive feedbackIGF1R, IR,Negative feedback target:IRS1, IRS2
	Casein Kinase-2 (CK2)CK2A1:Catal. Sub A1CK2A2:Catal. Sub A2CK2B: regulat. Sub B	CK2A1: T13CK2A2: TBDCK2B: S2, S3,	PKC, UBF, TIFI, MBM-cMYC, PTEN
	CyclinD1/D2	CCND1: T286CCND2: T280	AKT^S473
	Cyclin E1/E2	CCNE1: T395CCNE2: (S21)	Rb1/2, Frap1, Mybl1, Dmrtc2
	P21^CIP1	T145, S146	PCNA, TAF1
	P27^KIP1	T157	AURORA-K, RB2p130
	RbRb2 (p107, p130)	RB1: S780, S807, T821RB2: (S639, T642, T986, S1035)	SL1(RPol-I), SNAc(RPol-III)E2F, Pin1
	TP53	(S15, S20, S33, S46, T55)	Suppresses IGF-I, IGFII, IGFIR and InsR genes transcriptionSuppresses RPol-I transcription
	MDM2	S166, S186, S188	p53, IGF1R
	RPol-I (190 subunit)	TBD	rDNA gene(UBF/TIF1A-RRN3, TIFI63, TIFI110)
	UBF1 (RPol-I core TF)	(T9, S23, K61, K71, T117, K132, K144, K160, T201, K216, K232, K266, S273, K279, K352, S389, S412, S433, S449, K480, S484, S495, S546, S584, S638)	rDNA gene promotervia RPol-I and other associated TFs
	RRN3/TIF-IA(RPol-I core TF)	(S44, K75, S170, S172, S199, T200, K610, S633, S635, S636, S640, S649)	rDNA gene promotervia RPOL-I and other associated TFs
	TAF1 (TAFII250)	TBD	TFIID (RPol-II)UBF (RPol-I)
	TAFII150 (RPol-II)	TBD	CyclinD1 transcription via SP1
	RPol-III (220 subunit)	TBD	ERK activates tRNA synthesis by RPOL-III by phosphorylating TFIIIB
	MAF1 (RPol-III)	S60, T64, S65, S68, S70, S73, K74, S75, S85, S89, T212, S214	RPol-III regulated genes
	JunFos	Jun: S63Fos: (T232,, S362)	CyclinD, sox6, jun-d, gadd45a, and tob1, YAP/TAZ
	MycMax	MYC: T58, S62MAX: (S2, S11)	Myc: rDNA gene/Pol-I transcription, E2FMyc/Max: p27kip1 CyclinE, CDK2, CDK4
	FOXO1AFOXO3A	FOXOA1: T24, S256, S319, S322, S325, S329FOXO3A: T32, S253, S315, S318, S321	CyclinD1/D2, p21^CIP1, p27^KIP1,MDM2, 4EBPNegative feedback target:InsR

Figure 4. Proposed relationship between cellular growth, cell division and relative Polymerases activities in response to the Insulin/IGF proliferative signal. Refer to text for further explanation. [337](renumber to 336).

Scalia P, Giordano A, Williams SJ. The IGF-II-Insulin Receptor Isoform-A; Autocrine Signal in Cancer: Actionable Perspectives. Cancers (Basel). 2020 Feb 5;12(2):366.

 PubMed Web of Science ®Google Scholar

Baker J, Liu JP, Robertson EJ, et al. Role of insulin-like growth factors in embryonic and postnatal growth. Cell. 1993 Oct 8;75(1):73–82.

 PubMed Web of Science ®Google Scholar

Zhang H, Liu J, Li CR, et al. Deletion of Drosophila insulin-like peptides causes growth defects and metabolic abnormalities. Proc Natl Acad Sci U S A. 2009 Nov 17;106(46):19617–19622.

 PubMed Web of Science ®Google Scholar

Louvi A, Accili D, Efstratiadis A. Growth-promoting interaction of IGF-II with the insulin receptor during mouse embryonic development. Dev Biol. 1997 Sep 1;189(1):33–48.

 PubMed Web of Science ®Google Scholar

Oldham S, Stocker H, Laffargue M, et al. The Drosophila insulin/IGF receptor controls growth and size by modulating PtdInsP3 levels. Development. 2002;129(17):4103–4109.

 PubMed Web of Science ®Google Scholar

Accili D, Drago J, Lee EJ, et al. Early neonatal death in mice homozygous for a null allele of the insulin receptor gene. Nat Genet. 1996 Jan;12(1):106–109.

 PubMed Web of Science ®Google Scholar

Brogiolo W, Stocker H, Ikeya T, et al. An evolutionarily conserved function of the Drosophila insulin receptor and insulin-like peptides in growth control. Curr Biol. 2001 Feb 20;11(4):213–221.

 PubMed Web of Science ®Google Scholar

Lau MM, Stewart CE, Liu Z, et al. Loss of the imprinted IGF2/cation-independent mannose 6-phosphate receptor results in fetal overgrowth and perinatal lethality. Genes Dev. 1994 Dec 15;8(24):2953–2963.

 PubMed Web of Science ®Google Scholar

Araki E, Lipes MA, Patti ME, et al. Alternative pathway of insulin signalling in mice with targeted disruption of the IRS-1 gene. Nature. 1994 Nov 10;372(6502):186–190.

 PubMed Web of Science ®Google Scholar

Sun XJ, Wang L-M, Zhang Y, et al. Role of IRS-2 in insulin and cytokine signalling. Nature. 1995 Sep 01;377(6545):173–177.

 PubMed Web of Science ®Google Scholar

Bohni R, Riesgo-Escovar J, Oldham S, et al. Autonomous control of cell and organ size by CHICO, a Drosophila homolog of vertebrate IRS1-4. Cell. 1999 Jun 25;97(7):865–875.

 PubMed Web of Science ®Google Scholar

Leevers SJ, Weinkove D, MacDougall LK, et al. The Drosophila phosphoinositide 3-kinase Dp110 promotes cell growth. EMBO J. 1996;15(23):6584–6594.

 PubMed Web of Science ®Google Scholar

Lawlor MA, Mora A, Ashby PR, et al. Essential role of PDK1 in regulating cell size and development in mice. EMBO J. 2002;21(14):3728–3738.

 PubMed Web of Science ®Google Scholar

Cristofano AD, Pesce B, Cordon-Cardo C, et al. Pten is essential for embryonic development and tumour suppression. Nat Genet. 1998 Aug 01;19(4):348–355.

 PubMed Web of Science ®Google Scholar

Goberdhan DC, Paricio N, Goodman EC, et al. Drosophila tumor suppressor PTEN controls cell size and number by antagonizing the Chico/PI3-kinase signaling pathway. Genes Dev. 1999;13(24):3244–3258.

 PubMed Web of Science ®Google Scholar

Gao X, Pan D. TSC1 and TSC2 tumor suppressors antagonize insulin signaling in cell growth. Genes Dev. 2001 Jun 1;15(11):1383–1392.

 PubMed Web of Science ®Google Scholar

Rosner M, Hofer K, Kubista M, et al. Cell size regulation by the human TSC tumor suppressor proteins depends on PI3K and FKBP38. Oncogene. 2003 Jul 31;22(31):4786–4798.

 PubMed Web of Science ®Google Scholar

Potter CJ, Huang H, Xu T. Drosophila Tsc1 functions with Tsc2 to antagonize insulin signaling in regulating cell growth, cell proliferation, and organ size. Cell. 2001 May 4;105(3):357–368.

 PubMed Web of Science ®Google Scholar

Guertin DA, Stevens DM, Thoreen CC, et al. Ablation in mice of the mTORC components raptor, rictor, or mLST8 reveals that mTORC2 is required for signaling to Akt-FOXO and PKCalpha, but not S6K1. Dev Cell. 2006 Dec;11(6):859–871.

 PubMed Web of Science ®Google Scholar

Zhang H, Stallock JP, Ng JC, et al. Regulation of cellular growth by the Drosophila target of rapamycin dTOR. Genes Dev. 2000;14(21):2712–2724.

 PubMed Web of Science ®Google Scholar

Tanabe K, Liu Z, Patel S, et al. Genetic deficiency of glycogen synthase kinase-3beta corrects diabetes in mouse models of insulin resistance. PLoS Biol. 2008 Feb;6(2):e37.

 PubMed Web of Science ®Google Scholar

Doble BW, Patel S, Wood GA, et al. Functional redundancy of GSK-3alpha and GSK-3beta in Wnt/beta-catenin signaling shown by using an allelic series of embryonic stem cell lines. Dev Cell. 2007 Jun;12(6):957–971.

 PubMed Web of Science ®Google Scholar

Hoeflich KP, Luo J, Rubie EA, et al. Requirement for glycogen synthase kinase-3β in cell survival and NF-κB activation. Nature. 2000 Jul 01;406(6791):86–90.

 PubMed Web of Science ®Google Scholar

Tsukiyama-Kohara K, Poulin F, Kohara M, et al. Adipose tissue reduction in mice lacking the translational inhibitor 4E-BP1. Nat Med. 2001 Oct 01;7(10):1128–1132.

 PubMed Web of Science ®Google Scholar

Teleman AA, Chen Y-W, Cohen SM. 4E-BP functions as a metabolic brake used under stress conditions but not during normal growth. Genes Dev. 2005;19(16):1844–1848.

 PubMed Web of Science ®Google Scholar

Shima H, Pende M, Chen Y, et al. Disruption of the p70(s6k)/p85(s6k) gene reveals a small mouse phenotype and a new functional S6 kinase. EMBO J. 1998 Nov 16;17(22):6649–6659.

 PubMed Web of Science ®Google Scholar

Montagne J, Stewart MJ, Stocker H, et al. Drosophila S6 Kinase: A Regulator of Cell Size. Science. 1999;285(5436):2126–2129.

 PubMed Web of Science ®Google Scholar

Junger MA, Rintelen F, Stocker H, et al. The Drosophila forkhead transcription factor FOXO mediates the reduction in cell number associated with reduced insulin signaling. J Biol. 2003;2(3):20.

 PubMedGoogle Scholar

Hosaka T, Biggs WH 3rd, Tieu D, et al. Disruption of forkhead transcription factor (FOXO) family members in mice reveals their functional diversification. Proc Natl Acad Sci U S A. 2004;101(9):2975–2980.

 PubMed Web of Science ®Google Scholar

Hanke S, Mann M. The phosphotyrosine interactome of the insulin receptor family and its substrates IRS-1 and IRS-2. Mol Cell Proteomics. 2009 Mar;8(3):519–534.

 PubMed Web of Science ®Google Scholar

Data Availability Statement

Data sharing is not applicable to this article as no new data were created or analyzed in this study.