Table 1.

Overview of MAPK/ERK pathway in vertebrate organ regeneration.

Organs	(Species)	Signaling Components	Functions	References
Limb	(newt)	‑ERK/p53/sox6	‑Promote cell cycle progression and dedifferentiation	[33]
	(newt)	‑Prod1/EGFR/ERK/MMP9	‑Promote WE and blastema formation	[34]
	(Xenopus laevis)	‑MAPK/ERK1/2 and PI3K/Akt pathways	‑Promote blastema formation	[35]
Tail	(axolotl)	‑anoctamin1/ERK1/2	‑Promote cell proliferation	[36]
	(Xenopus laevis)	‑ERK/TGF-β/ROS	‑Promote wound healing	[37]
	(zebrafish)	‑ERK	‑Promote regeneration	[38]
Fin	(zebrafish)	‑FGF/ERK1/2&Wnt/β-catenin/raldh2	‑Promote WE and blastema formation	[39]
		‑FGF/ERK1/2&Wnt/β-catenin	‑Promote cell proliferation	[40]
			‑Promote regeneration initiation
Scale	(zebrafish)	‑ERK activity wave	‑Control scale morphogenesis	[41]
		‑Melatonin/ inhibiting ERK1/2	‑Suppress osteoblast and osteoclast differentiation	[42]
Antler	(deer)	‑PAP/InsR/IRS-1/ERK and PAP/PI3K/Akt	‑Promote osteoblasts proliferation, differentiation, and mineralization	[43]
		‑ERK/MAPK, PI3K/Akt and p38 MAPK		[44]
Heart	(zebrafish)	‑Duox&Nox2/H2O2/Dusp6/ERK1/2	‑Promote CM proliferation, coronary angiogenesis	[45]
		‑Dusp6/Ras/MAPK	‑Reduce fibrosis	[46]
	(mice)	‑ERBB2/ERK/YAP	‑Reactivate adult mice CM dedifferentiation, proliferation, and migration	[47]
		‑ERBB2/ERK	‑Promote CM dedifferentiation, proliferation, and redifferentiation	[48]
		‑Agrin/ Dag1 /ERK&YAP	‑Induce adult/juvenile mice CM dedifferentiation, maturation, and proliferation	[49]
		‑N-Cadherin/ERK/VEGF	‑Promote coronary angiogenesis and CM integration	[50]
		‑LPA/LPA3/ERK	‑Promote CM proliferation	[51]
	(rat)	‑ERBB2/ERK	‑Induce CM proliferation, sarcomere loss, and tissue remodeling	[52]
		‑E2F1/ECRAR/ERK1/2 positive feedback loop	‑Promote adult CM proliferation	[53]
Liver	(axolotl)	‑ERK activation	‑Promote hepatocyte proliferation	[54]
	(mice)	‑Serotonin/ERK/YAP	‑Promote hepatocyte proliferation	[55]
		‑IGF-1R/IRS-1/ERK/cyclin D1&A	‑Promote hepatocyte proliferation	[56,57]
		‑PKA/ERK, Wnt/β-catenin and NMII-Rac signaling	‑Promote liver organoid cholangiocyte-to-hepatocyte differentiation, Expansion, and ex vivo maintenance	[58]
		‑HGF/MET/ERK1/2, inhibition of TGF-β and GSK3 signaling	‑Promote human hepatocytes cell fate turnover and proliferation	[59]
		‑GHR/EGFR/ERK1/2	‑Promote hepatocytes cell G1/S phase transition	[60]
	(rat)	‑ERK1/2 & p70S6K	‑Promote hepatocyte and cholangiocyte proliferation	[61]
Eye	(zebrafish)	‑HB-EGF/EGFR/ERK1/2/ascl1a, c-mycb&pax6b	‑Promote MG dedifferentiation	[62]
		‑Insulin& HB-EGF, IGF-1& FGF2/ERK, PI3K/β-catenin and pStat3	‑Promote MG reprogramming and proliferation	[63]
	(newt)	‑MEK1/2/ERK1/2	‑Promote RPE cell cycle re-entry	[64,65,66]
		‑FGF2/MEK-ERK	‑Promote RPE transdifferentiation and proliferation	[67]
	(Xenopus laevis)	‑FGF2/MEK/ERK	‑Promote RPE transdifferentiation and proliferation	[68]
	(chick)	‑FGF2/FGFR/MEK/ERK/Pax6	‑Promote RPE transdifferentiation	[69]
PNS	(zebrafish)	‑H3K27me3 histone demethylase/ ERK1/2/p21&p27	‑Promote hair cell proliferation	[70]
			‑Promote neuromast proliferation and survival
	(mice)	‑Ras/Raf/MEK/ERK	‑Promote SC dedifferentiation, proliferation, and demyelination	[71,72]
			‑Suppress SC differentiation
			‑Recruit inflammatory cells
		‑Cell-autonomous MAPK/ERK1/2 activation in SCs	‑Increase SCs myelin sheath thickness	[73]
	(rat)	‑VEGF-A/VEGFR2/ERK	‑Promote angiogenesis	[74]
CNS	(frog)	‑RA/MAPK/ERK&AKT&STAT3	‑Promote RGC long-term survival	[75]
	(mice)	‑SORLA/EGFR/ERK/c-fos	‑Promote neurite outgrowth	[76]
		‑Bcl-2/Ca2+ influx/ERK/CREB	‑Promote neuronal survival and neurite outgrowth	[24]
		‑MAPK/ERK1/2 activation	‑Promote OPC differentiation and remyelination	[77]
		‑Cell-autonomous MAPK/ERK1/2 activation in OLs/ OPCs	‑Increase OLs myelin sheath thickness and OPCs proliferation	[73,78]
		‑EGFR/ERK/decreased TRIM32	‑Suppress NSC differentiation	[79]
	(rat)	‑BDNF/trkB/ERK/CREB	‑Promote neurite outgrowth	[80]
		‑Intracellular Sigma Peptide/ERK/CREB	‑Promote axon regrowth and neuron functional recovery	[81]
		‑ERK/MAPK	‑Promote axon regrowth	[82]

WE, wound epidermis; EGFR, epidermal growth factor receptor; MMP9, matrix metallopeptidase 9; Akt, protein kinase B; raldh2, retinal dehydrogenase 2; PAP, pilose antler peptide; InsR, insulin receptor; Duox, dual oxidase 2; Nox2, NADPH-oxidase 2; ERBB2, Erb-B2 receptor tyrosine kinase 2; NRG1, neuregulin 1; Dag1, α-dystroglycan; LPA, lysophosphatidic acid; E2F1, E2F transcription factor 1; IGF-1R, insulin-like growth factor type 1 receptor; PKA, protein kinase A; NMII, non-muscle myosin II; HGF, hepatocyte growth factor; GHR, growth hormone receptor; HB-EGF, heparin-binding EGF-like growth factor; pax6_b, paired box 6_b; PAX6, paired box 6; H3K27me3, tri-methylation of histone H3 at lysine 27; VEGFR2, vascular endothelial growth factor receptor 2; SORLA, sortilin-related receptor with A-type repeats; ISP, intracellular sigma peptide; CREB, the cAMP-response element binding protein; CM, cardiomyocyte; NSC, neural stem cell; RA, retinoic acid; CNS, central nervous system; TRIM32, tripartite motif containing 32.