KEGG   PATHWAY: mmu04550Help
mmu04550                    Pathway                                

Signaling pathways regulating pluripotency of stem cells - Mus musculus (mouse)
Pluripotent stem cells (PSCs) are basic cells with an indefinite self-renewal capacity and the potential to generate all the cell types of the three germinal layers. The types of PSCs known to date include embryonic stem (ES) and induced pluripotent stem (iPS) cells. ES cells are derived from the inner cell mass (ICM) of blastocyst-stage embryos. iPS cells are generated by reprogramming somatic cells back to pluripotent state with defined reprogramming factors, Oct4, Sox2, Klf4 and c-Myc (also known as Yamanaka factors). PSCs including ES cells and iPS cells are categorized into two groups by their morphology, gene expression profile and external signal dependence. Conventional mouse-type ES/iPS cells are called 'naive state' cells. They are mainly maintained under the control of LIF and BMP signaling. On the other hand, human-type ES/iPS cells, which are in need of Activin and FGF signaling, are termed 'primed state'. However, these signaling pathways converge towards the activation of a core transcriptional network that is similar in both groups and involves OCt4, Nanog and Sox2. The three transcription factors and their downstream target genes coordinately promote self-renewal and pluripotency.
Cellular Processes; Cellular community - eukaryotes
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Pathway map
mmu04550  Signaling pathways regulating pluripotency of stem cells

Ortholog table
Other DBs
GO: 2000036
Mus musculus (mouse) [GN:mmu]
16878  Lif; leukemia inhibitory factor [KO:K05419]
16880  Lifr; LIF receptor alpha [KO:K05058]
16195  Il6st; interleukin 6 signal transducer [KO:K05060]
16451  Jak1; Janus kinase 1 [KO:K11217] [EC:]
16452  Jak2; Janus kinase 2 [KO:K04447] [EC:]
16453  Jak3; Janus kinase 3 [KO:K11218] [EC:]
20848  Stat3; signal transducer and activator of transcription 3 [KO:K04692]
16600  Klf4; Kruppel-like factor 4 (gut) [KO:K17846]
20674  Sox2; SRY (sex determining region Y)-box 2 [KO:K16796]
17869  Myc; myelocytomatosis oncogene [KO:K04377]
14784  Grb2; growth factor receptor bound protein 2 [KO:K04364]
26395  Map2k1; mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:]
26396  Map2k2; mitogen-activated protein kinase kinase 2 [KO:K04369] [EC:]
26413  Mapk1; mitogen-activated protein kinase 1 [KO:K04371] [EC:]
26417  Mapk3; mitogen-activated protein kinase 3 [KO:K04371] [EC:]
18706  Pik3ca; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha [KO:K00922] [EC:]
18707  Pik3cd; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta [KO:K00922] [EC:]
74769  Pik3cb; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta [KO:K00922] [EC:]
18709  Pik3r2; phosphoinositide-3-kinase regulatory subunit 2 [KO:K02649]
18708  Pik3r1; phosphoinositide-3-kinase regulatory subunit 1 [KO:K02649]
18710  Pik3r3; phosphoinositide-3-kinase regulatory subunit 3 [KO:K02649]
11651  Akt1; thymoma viral proto-oncogene 1 [KO:K04456] [EC:]
11652  Akt2; thymoma viral proto-oncogene 2 [KO:K04456] [EC:]
23797  Akt3; thymoma viral proto-oncogene 3 [KO:K04456] [EC:]
21386  Tbx3; T-box 3 [KO:K10177]
71950  Nanog; Nanog homeobox [KO:K10164]
16323  Inhba; inhibin beta-A [KO:K04667]
16324  Inhbb; inhibin beta-B [KO:K22687]
16325  Inhbc; inhibin beta-C [KO:K22688]
16326  Inhbe; inhibin beta-E [KO:K22689]
18119  Nodal; nodal [KO:K04666]
11479  Acvr1b; activin A receptor, type 1B [KO:K13567] [EC:]
269275  Acvr1c; activin A receptor, type IC [KO:K13568] [EC:]
11481  Acvr2b; activin receptor IIB [KO:K13596] [EC:]
11480  Acvr2a; activin receptor IIA [KO:K13596] [EC:]
17126  Smad2; SMAD family member 2 [KO:K04500]
17127  Smad3; SMAD family member 3 [KO:K23605]
12159  Bmp4; bone morphogenetic protein 4 [KO:K04662]
12166  Bmpr1a; bone morphogenetic protein receptor, type 1A [KO:K04673] [EC:]
12167  Bmpr1b; bone morphogenetic protein receptor, type 1B [KO:K13578] [EC:]
11477  Acvr1; activin A receptor, type 1 [KO:K04675] [EC:]
12168  Bmpr2; bone morphogenetic protein receptor, type II (serine/threonine kinase) [KO:K04671] [EC:]
17125  Smad1; SMAD family member 1 [KO:K04676]
17129  Smad5; SMAD family member 5 [KO:K16790]
55994  Smad9; SMAD family member 9 [KO:K16791]
17128  Smad4; SMAD family member 4 [KO:K04501]
15901  Id1; inhibitor of DNA binding 1, HLH protein [KO:K04680]
15902  Id2; inhibitor of DNA binding 2 [KO:K17693]
15903  Id3; inhibitor of DNA binding 3 [KO:K17694]
15904  Id4; inhibitor of DNA binding 4 [KO:K17695]
75590  Dusp9; dual specificity phosphatase 9 [KO:K18498] [EC:]
26416  Mapk14; mitogen-activated protein kinase 14 [KO:K04441] [EC:]
19094  Mapk11; mitogen-activated protein kinase 11 [KO:K04441] [EC:]
29857  Mapk12; mitogen-activated protein kinase 12 [KO:K04441] [EC:]
26415  Mapk13; mitogen-activated protein kinase 13 [KO:K04441] [EC:]
22408  Wnt1; wingless-type MMTV integration site family, member 1 [KO:K03209]
22413  Wnt2; wingless-type MMTV integration site family, member 2 [KO:K00182]
22414  Wnt2b; wingless-type MMTV integration site family, member 2B [KO:K00182]
22415  Wnt3; wingless-type MMTV integration site family, member 3 [KO:K00312]
22416  Wnt3a; wingless-type MMTV integration site family, member 3A [KO:K00312]
22417  Wnt4; wingless-type MMTV integration site family, member 4 [KO:K00408]
22418  Wnt5a; wingless-type MMTV integration site family, member 5A [KO:K00444]
22419  Wnt5b; wingless-type MMTV integration site family, member 5B [KO:K00444]
22420  Wnt6; wingless-type MMTV integration site family, member 6 [KO:K00445]
22421  Wnt7a; wingless-type MMTV integration site family, member 7A [KO:K00572]
22422  Wnt7b; wingless-type MMTV integration site family, member 7B [KO:K00572]
20890  Wnt8a; wingless-type MMTV integration site family, member 8A [KO:K00714]
22423  Wnt8b; wingless-type MMTV integration site family, member 8B [KO:K00714]
216795  Wnt9a; wingless-type MMTV integration site family, member 9A [KO:K01064]
22412  Wnt9b; wingless-type MMTV integration site family, member 9B [KO:K01064]
22410  Wnt10b; wingless-type MMTV integration site family, member 10B [KO:K01357]
22409  Wnt10a; wingless-type MMTV integration site family, member 10A [KO:K01357]
22411  Wnt11; wingless-type MMTV integration site family, member 11 [KO:K01384]
93735  Wnt16; wingless-type MMTV integration site family, member 16 [KO:K01558]
14362  Fzd1; frizzled class receptor 1 [KO:K02432]
14369  Fzd7; frizzled class receptor 7 [KO:K02432]
57265  Fzd2; frizzled class receptor 2 [KO:K02235]
14365  Fzd3; frizzled class receptor 3 [KO:K02329]
14366  Fzd4; frizzled class receptor 4 [KO:K02354]
14367  Fzd5; frizzled class receptor 5 [KO:K02375]
14370  Fzd8; frizzled class receptor 8 [KO:K02375]
14368  Fzd6; frizzled class receptor 6 [KO:K02376]
93897  Fzd10; frizzled class receptor 10 [KO:K02842]
14371  Fzd9; frizzled class receptor 9 [KO:K02842]
13544  Dvl3; dishevelled segment polarity protein 3 [KO:K02353]
13542  Dvl1; dishevelled segment polarity protein 1 [KO:K02353]
13543  Dvl2; dishevelled segment polarity protein 2 [KO:K02353]
56637  Gsk3b; glycogen synthase kinase 3 beta [KO:K03083] [EC:]
12005  Axin1; axin 1 [KO:K02157]
12006  Axin2; axin 2 [KO:K04385]
11789  Apc; APC, WNT signaling pathway regulator [KO:K02085]
23805  Apc2; adenomatosis polyposis coli 2 [KO:K02085]
12387  Ctnnb1; catenin (cadherin associated protein), beta 1 [KO:K02105]
21423  Tcf3; transcription factor 3 [KO:K09063]
26380  Esrrb; estrogen related receptor, beta [KO:K08553]
21414  Tcf7; transcription factor 7, T cell specific [KO:K02620]
18999  Pou5f1; POU domain, class 5, transcription factor 1 [KO:K09367]
14173  Fgf2; fibroblast growth factor 2 [KO:K18497]
14182  Fgfr1; fibroblast growth factor receptor 1 [KO:K04362] [EC:]
14183  Fgfr2; fibroblast growth factor receptor 2 [KO:K05093] [EC:]
14184  Fgfr3; fibroblast growth factor receptor 3 [KO:K05094] [EC:]
14186  Fgfr4; fibroblast growth factor receptor 4 [KO:K05095] [EC:]
15461  Hras; Harvey rat sarcoma virus oncogene [KO:K02833]
16653  Kras; Kirsten rat sarcoma viral oncogene homolog [KO:K07827]
18176  Nras; neuroblastoma ras oncogene [KO:K07828]
110157  Raf1; v-raf-leukemia viral oncogene 1 [KO:K04366] [EC:]
16000  Igf1; insulin-like growth factor 1 [KO:K05459]
16001  Igf1r; insulin-like growth factor I receptor [KO:K05087] [EC:]
15209  Hesx1; homeobox gene expressed in ES cells [KO:K09354]
22773  Zic3; zinc finger protein of the cerebellum 3 [KO:K18487]
13590  Lefty1; left right determination factor 1 [KO:K04668]
320202  Lefty2; left-right determination factor 2 [KO:K04668]
20482  Skil; SKI-like [KO:K18499]
13990  Smarcad1; SWI/SNF-related, matrix-associated actin-dependent regulator of chromatin, subfamily a, containing DEAD/H box 1 [KO:K14439] [EC:]
244349  Kat6a; K(lysine) acetyltransferase 6A [KO:K11305] [EC:]
84505  Setdb1; SET domain, bifurcated 1 [KO:K11421] [EC:]
16468  Jarid2; jumonji, AT rich interactive domain 2 [KO:K11478]
19712  Rest; RE1-silencing transcription factor [KO:K09222]
51869  Rif1; replication timing regulatory factor 1 [KO:K11138]
69837  Pcgf1; polycomb group ring finger 1 [KO:K11487]
22658  Pcgf2; polycomb group ring finger 2 [KO:K11460]
69587  Pcgf3; polycomb group ring finger 3 [KO:K11488]
12151  Bmi1; Bmi1 polycomb ring finger oncogene [KO:K11459]
76073  Pcgf5; polycomb group ring finger 5 [KO:K11489]
71041  Pcgf6; polycomb group ring finger 6 [KO:K11470]
18508  Pax6; paired box 6 [KO:K08031]
17268  Meis1; Meis homeobox 1 [KO:K15613]
16873  Lhx5; LIM homeobox protein 5 [KO:K18493]
18423  Otx1; orthodenticle homeobox 1 [KO:K09326]
18014  Neurog1; neurogenin 1 [KO:K09081]
15110  Hand1; heart and neural crest derivatives expressed 1 [KO:K09071]
13395  Dlx5; distal-less homeobox 5 [KO:K18489]
17877  Myf5; myogenic factor 5 [KO:K18484]
15379  Onecut1; one cut domain, family member 1 [KO:K08026]
16392  Isl1; ISL1 transcription factor, LIM/homeodomain [KO:K09370]
11906  Zfhx3; zinc finger homeobox 3 [KO:K09378]
13984  Esx1; extraembryonic, spermatogenesis, homeobox 1 [KO:K18491]
15407  Hoxb1; homeobox B1 [KO:K09301]
Bhartiya D, Lenka N (ed).
Pluripotent Stem Cells
InTech (2013)
Hassani SN, Totonchi M, Gourabi H, Scholer HR, Baharvand H
Signaling roadmap modulating naive and primed pluripotency.
Stem Cells Dev 23:193-208 (2014)
Jaenisch R, Young R
Stem cells, the molecular circuitry of pluripotency and nuclear reprogramming.
Cell 132:567-82 (2008)
Zhang H, Wang ZZ
Mechanisms that mediate stem cell self-renewal and differentiation.
J Cell Biochem 103:709-18 (2008)
Itoh F, Watabe T, Miyazono K
Roles of TGF-beta family signals in the fate determination of pluripotent stem cells.
Semin Cell Dev Biol 32C:98-106 (2014)
Saunders A, Faiola F, Wang J
Concise review: pursuing self-renewal and pluripotency with the stem cell factor Nanog.
Stem Cells 31:1227-36 (2013)
Kuijk EW, Chuva de Sousa Lopes SM, Geijsen N, Macklon N, Roelen BA
The different shades of mammalian pluripotent stem cells.
Hum Reprod Update 17:254-71 (2011)
Okita K, Yamanaka S
Intracellular signaling pathways regulating pluripotency of embryonic stem cells.
Curr Stem Cell Res Ther 1:103-11 (2006)
Niwa H, Ogawa K, Shimosato D, Adachi K
A parallel circuit of LIF signalling pathways maintains pluripotency of mouse ES cells.
Nature 460:118-22 (2009)
Nakai-Futatsugi Y, Niwa H
Transcription factor network in embryonic stem cells: heterogeneity under the stringency.
Biol Pharm Bull 36:166-70 (2013)
Medvedev SP, Shevchenko AI, Zakian SM
Molecular basis of Mammalian embryonic stem cell pluripotency and self-renewal.
Acta Naturae 2:30-46 (2010)
Scheper W, Copray S
The molecular mechanism of induced pluripotency: a two-stage switch.
Stem Cell Rev 5:204-23 (2009)
Boyer LA, Lee TI, Cole MF, Johnstone SE, Levine SS, Zucker JP, Guenther MG, Kumar RM, Murray HL, Jenner RG, Gifford DK, Melton DA, Jaenisch R, Young RA
Core transcriptional regulatory circuitry in human embryonic stem cells.
Cell 122:947-56 (2005)
Wang L, Miao YL, Zheng X, Lackford B, Zhou B, Han L, Yao C, Ward JM, Burkholder A, Lipchina I, Fargo DC, Hochedlinger K, Shi Y, Williams CJ, Hu G
The THO complex regulates pluripotency gene mRNA export and controls embryonic stem cell self-renewal and somatic cell reprogramming.
Cell Stem Cell 13:676-90 (2013)
Hasegawa Y, Tang D, Takahashi N, Hayashizaki Y, Forrest AR, Suzuki H
CCL2 enhances pluripotency of human induced pluripotent stem cells by activating hypoxia related genes.
Sci Rep 4:5228 (2014)
Sui L, Bouwens L, Mfopou JK
Signaling pathways during maintenance and definitive endoderm differentiation of embryonic stem cells.
Int J Dev Biol 57:1-12 (2013)
Do JT, Scholer HR
Regulatory circuits underlying pluripotency and reprogramming.
Trends Pharmacol Sci 30:296-302 (2009)
Pan G, Thomson JA
Nanog and transcriptional networks in embryonic stem cell pluripotency.
Cell Res 17:42-9 (2007)
Loh YH, Wu Q, Chew JL, Vega VB, Zhang W, Chen X, Bourque G, George J, Leong B, Liu J, Wong KY, Sung KW, Lee CW, Zhao XD, Chiu KP, Lipovich L, Kuznetsov VA, Robson P, Stanton LW, Wei CL, Ruan Y, Lim B, Ng HH
The Oct4 and Nanog transcription network regulates pluripotency in mouse embryonic stem cells.
Nat Genet 38:431-40 (2006)
Loh YH, Ng JH, Ng HH
Molecular framework underlying pluripotency.
Cell Cycle 7:885-91 (2008)
Greenow K, Clarke AR
Controlling the stem cell compartment and regeneration in vivo: the role of pluripotency pathways.
Physiol Rev 92:75-99 (2012)
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