KEGG PATHWAY: mmu04550

PATHWAY: mmu04550

Entry

mmu04550                    Pathway

Name

Signaling pathways regulating pluripotency of stem cells - Mus musculus (house mouse)

Description

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.

Class

Cellular Processes; Cellular community - eukaryotes

Pathway map

mmu04550

Signaling pathways regulating pluripotency of stem cells

Other DBs

GO:

2000036

Organism

Mus musculus (house mouse) [GN:mmu]

Gene

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:2.7.10.2]

16452

Jak2; Janus kinase 2 [KO:K04447] [EC:2.7.10.2]

16453

Jak3; Janus kinase 3 [KO:K11218] [EC:2.7.10.2]

20848

Stat3; signal transducer and activator of transcription 3 [KO:K04692]

16600

Klf4; Kruppel-like transcription 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:2.7.12.2]

26396

Map2k2; mitogen-activated protein kinase kinase 2 [KO:K04369] [EC:2.7.12.2]

26413

Mapk1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]

26417

Mapk3; mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]

18706

Pik3ca; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha [KO:K00922] [EC:2.7.1.153]

18707

Pik3cd; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta [KO:K00922] [EC:2.7.1.153]

74769

Pik3cb; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta [KO:K00922] [EC:2.7.1.153]

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:2.7.11.1]

11652

Akt2; thymoma viral proto-oncogene 2 [KO:K04456] [EC:2.7.11.1]

23797

Akt3; thymoma viral proto-oncogene 3 [KO:K04456] [EC:2.7.11.1]

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:2.7.11.30]

269275

Acvr1c; activin A receptor, type IC [KO:K13568] [EC:2.7.11.30]

11480

Acvr2a; activin receptor IIA [KO:K04670] [EC:2.7.11.30]

11481

Acvr2b; activin receptor IIB [KO:K13596] [EC:2.7.11.30]

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:2.7.11.30]

12167

Bmpr1b; bone morphogenetic protein receptor, type 1B [KO:K13578] [EC:2.7.11.30]

11477

Acvr1; activin A receptor, type 1 [KO:K04675] [EC:2.7.11.30]

12168

Bmpr2; bone morphogenetic protein receptor type 2 [KO:K04671] [EC:2.7.11.30]

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:3.1.3.16 3.1.3.48]

26416

Mapk14; mitogen-activated protein kinase 14 [KO:K04441] [EC:2.7.11.24]

19094

Mapk11; mitogen-activated protein kinase 11 [KO:K04441] [EC:2.7.11.24]

29857

Mapk12; mitogen-activated protein kinase 12 [KO:K04441] [EC:2.7.11.24]

26415

Mapk13; mitogen-activated protein kinase 13 [KO:K04441] [EC:2.7.11.24]

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:2.7.11.26]

12005

Axin1; axin 1 [KO:K02157]

12006

Axin2; axin 2 [KO:K04385]

11789

Apc; APC, WNT signaling pathway regulator [KO:K02085]

23805

Apc2; APC regulator of WNT signaling pathway 2 [KO:K02085]

12387

Ctnnb1; catenin 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:2.7.10.1]

14183

Fgfr2; fibroblast growth factor receptor 2 [KO:K05093] [EC:2.7.10.1]

14184

Fgfr3; fibroblast growth factor receptor 3 [KO:K05094] [EC:2.7.10.1]

14186

Fgfr4; fibroblast growth factor receptor 4 [KO:K05095] [EC:2.7.10.1]

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:2.7.11.1]

16000

Igf1; insulin-like growth factor 1 [KO:K05459]

16001

Igf1r; insulin-like growth factor I receptor [KO:K05087] [EC:2.7.10.1]

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:5.6.2.-]

244349

Kat6a; K(lysine) acetyltransferase 6A [KO:K11305] [EC:2.3.1.48]

84505

Setdb1; SET domain, bifurcated 1 [KO:K11421] [EC:2.1.1.366]

16468

Jarid2; jumonji and AT-rich interaction domain containing 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]

15407

Hoxb1; homeobox B1 [KO:K09301]

15394

Hoxa1; homeobox A1 [KO:K09301]

15429

Hoxd1; homeobox D1 [KO:K09301]

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]

Reference

Authors

Bhartiya D, Lenka N (ed).

Title

Pluripotent Stem Cells

Journal

InTech (2013)
DOI:10.5772/45917

Reference

PMID:24147644

Authors

Hassani SN, Totonchi M, Gourabi H, Scholer HR, Baharvand H

Title

Signaling roadmap modulating naive and primed pluripotency.

Journal

Stem Cells Dev 23:193-208 (2014)
DOI:10.1089/scd.2013.0368

Reference

PMID:18295576

Authors

Jaenisch R, Young R

Title

Stem cells, the molecular circuitry of pluripotency and nuclear reprogramming.

Journal

Cell 132:567-82 (2008)
DOI:10.1016/j.cell.2008.01.015

Reference

PMID:17647265

Authors

Zhang H, Wang ZZ

Title

Mechanisms that mediate stem cell self-renewal and differentiation.

Journal

J Cell Biochem 103:709-18 (2008)
DOI:10.1002/jcb.21460

Reference

PMID:24910449

Authors

Itoh F, Watabe T, Miyazono K

Title

Roles of TGF-beta family signals in the fate determination of pluripotent stem cells.

Journal

Semin Cell Dev Biol 32C:98-106 (2014)
DOI:10.1016/j.semcdb.2014.05.017

Reference

PMID:23653415

Authors

Saunders A, Faiola F, Wang J

Title

Concise review: pursuing self-renewal and pluripotency with the stem cell factor Nanog.

Journal

Stem Cells 31:1227-36 (2013)
DOI:10.1002/stem.1384

Reference

PMID:20705693

Authors

Kuijk EW, Chuva de Sousa Lopes SM, Geijsen N, Macklon N, Roelen BA

Title

The different shades of mammalian pluripotent stem cells.

Journal

Hum Reprod Update 17:254-71 (2011)
DOI:10.1093/humupd/dmq035

Reference

PMID:18220859

Authors

Okita K, Yamanaka S

Title

Intracellular signaling pathways regulating pluripotency of embryonic stem cells.

Journal

Curr Stem Cell Res Ther 1:103-11 (2006)
DOI:10.2174/157488806775269061

Reference

PMID:19571885

Authors

Niwa H, Ogawa K, Shimosato D, Adachi K

Title

A parallel circuit of LIF signalling pathways maintains pluripotency of mouse ES cells.

Journal

Nature 460:118-22 (2009)
DOI:10.1038/nature08113

Reference

PMID:23370346

Authors

Nakai-Futatsugi Y, Niwa H

Title

Transcription factor network in embryonic stem cells: heterogeneity under the stringency.

Journal

Biol Pharm Bull 36:166-70 (2013)
DOI:10.1248/bpb.b12-00958

Reference

PMID:22649650

Authors

Medvedev SP, Shevchenko AI, Zakian SM

Title

Molecular basis of Mammalian embryonic stem cell pluripotency and self-renewal.

Journal

Acta Naturae 2:30-46 (2010)

Reference

PMID:19551525

Authors

Scheper W, Copray S

Title

The molecular mechanism of induced pluripotency: a two-stage switch.

Journal

Stem Cell Rev 5:204-23 (2009)
DOI:10.1007/s12015-009-9077-x

Reference

PMID:16153702

Authors

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

Title

Core transcriptional regulatory circuitry in human embryonic stem cells.

Journal

Cell 122:947-56 (2005)
DOI:10.1016/j.cell.2005.08.020

Reference

PMID:24315442

Authors

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

Title

The THO complex regulates pluripotency gene mRNA export and controls embryonic stem cell self-renewal and somatic cell reprogramming.

Journal

Cell Stem Cell 13:676-90 (2013)
DOI:10.1016/j.stem.2013.10.008

Reference

PMID:24957798

Authors

Hasegawa Y, Tang D, Takahashi N, Hayashizaki Y, Forrest AR, Suzuki H

Title

CCL2 enhances pluripotency of human induced pluripotent stem cells by activating hypoxia related genes.

Journal

Sci Rep 4:5228 (2014)
DOI:10.1038/srep05228

Reference

PMID:23585347

Authors

Sui L, Bouwens L, Mfopou JK

Title

Signaling pathways during maintenance and definitive endoderm differentiation of embryonic stem cells.

Journal

Int J Dev Biol 57:1-12 (2013)
DOI:10.1387/ijdb.120115ls

Reference

PMID:19427042

Authors

Do JT, Scholer HR

Title

Regulatory circuits underlying pluripotency and reprogramming.

Journal

Trends Pharmacol Sci 30:296-302 (2009)
DOI:10.1016/j.tips.2009.03.003

Reference

PMID:17211451

Authors

Pan G, Thomson JA

Title

Nanog and transcriptional networks in embryonic stem cell pluripotency.

Journal

Cell Res 17:42-9 (2007)
DOI:10.1038/sj.cr.7310125

Reference

PMID:16518401

Authors

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

Title

The Oct4 and Nanog transcription network regulates pluripotency in mouse embryonic stem cells.

Journal

Nat Genet 38:431-40 (2006)
DOI:10.1038/ng1760

Reference

PMID:18414030

Authors

Loh YH, Ng JH, Ng HH

Title

Molecular framework underlying pluripotency.

Journal

Cell Cycle 7:885-91 (2008)
DOI:10.4161/cc.7.7.5636