KEGG PATHWAY: ko04550

PATHWAY: ko04550

Entry

ko04550                     Pathway

Name

Signaling pathways regulating pluripotency of stem cells

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

ko04550

Signaling pathways regulating pluripotency of stem cells

Other DBs

GO:

2000036

Orthology

K00182

WNT2; wingless-type MMTV integration site family, member 2

K00312

WNT3; wingless-type MMTV integration site family, member 3

K00408

WNT4; wingless-type MMTV integration site family, member 4

K00444

WNT5; wingless-type MMTV integration site family, member 5

K00445

WNT6; wingless-type MMTV integration site family, member 6

K00572

WNT7; wingless-type MMTV integration site family, member 7

K00714

WNT8; wingless-type MMTV integration site family, member 8

K00922

PIK3CA_B_D; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha/beta/delta [EC:2.7.1.153]

K01064

WNT9; wingless-type MMTV integration site family, member 9

K01357

WNT10; wingless-type MMTV integration site family, member 10

K01384

WNT11; wingless-type MMTV integration site family, member 11

K01558

WNT16; wingless-type MMTV integration site family, member 16

K02085

APC; adenomatosis polyposis coli protein

K02105

CTNNB1; catenin beta 1

K02157

AXIN1; axin 1

K02235

FZD2; frizzled 2

K02329

FZD3; frizzled 3

K02353

DVL; segment polarity protein dishevelled

K02354

FZD4, fz4, CD344; frizzled 4

K02375

FZD5_8, fz2; frizzled 5/8

K02376

FZD6; frizzled 6

K02432

FZD1_7, fz; frizzled 1/7

K02620

TCF7, TCF-1; transcription factor 7

K02649

PIK3R1_2_3; phosphoinositide-3-kinase regulatory subunit alpha/beta/delta

K02833

HRAS; GTPase HRas

K02842

FZD9_10, CD349_50; frizzled 9/10

K03083

GSK3B; glycogen synthase kinase 3 beta [EC:2.7.11.26]

K03209

WNT1; wingless-type MMTV integration site family, member 1

K04362

FGFR1, CD331; fibroblast growth factor receptor 1 [EC:2.7.10.1]

K04364

GRB2; growth factor receptor-bound protein 2

K04366

RAF1; RAF proto-oncogene serine/threonine-protein kinase [EC:2.7.11.1]

K04368

MAP2K1, MEK1; mitogen-activated protein kinase kinase 1 [EC:2.7.12.2]

K04369

MAP2K2, MEK2; mitogen-activated protein kinase kinase 2 [EC:2.7.12.2]

K04371

ERK, MAPK1_3; mitogen-activated protein kinase 1/3 [EC:2.7.11.24]

K04377

MYC; Myc proto-oncogene protein

K04385

AXIN2; axin 2

K04441

P38; p38 MAP kinase [EC:2.7.11.24]

K04447

JAK2; Janus kinase 2 [EC:2.7.10.2]

K04456

AKT; RAC serine/threonine-protein kinase [EC:2.7.11.1]

K04500

SMAD2; mothers against decapentaplegic homolog 2

K04501

SMAD4; mothers against decapentaplegic homolog 4

K04662

BMP4; bone morphogenetic protein 4

K04666

NODAL; nodal

K04667

INHBA; inhibin beta A chain

K04668

LEFTY; left-right determination factor

K04670

ACVR2A; activin receptor type-2A [EC:2.7.11.30]

K04671

BMPR2; bone morphogenetic protein receptor type-2 [EC:2.7.11.30]

K04673

BMPR1A, ALK3, CD292; bone morphogenetic protein receptor type-1A [EC:2.7.11.30]

K04675

ACVR1, ALK2; activin receptor type-1 [EC:2.7.11.30]

K04676

SMAD1; mothers against decapentaplegic homolog 1

K04680

ID1; DNA-binding protein inhibitor ID1

K04692

STAT3; signal transducer and activator of transcription 3

K05058

LIFR, CD118; leukemia inhibitory factor receptor

K05060

IL6ST, GP130, CD130; interleukin 6 signal transducer

K05087

IGF1R, CD221; insulin-like growth factor 1 receptor [EC:2.7.10.1]

K05093

FGFR2, CD332; fibroblast growth factor receptor 2 [EC:2.7.10.1]

K05094

FGFR3, CD333; fibroblast growth factor receptor 3 [EC:2.7.10.1]

K05095

FGFR4, CD334; fibroblast growth factor receptor 4 [EC:2.7.10.1]

K05419

LIF; leukemia inhibitory factor

K05459

IGF1; insulin-like growth factor 1

K07827

KRAS, KRAS2; GTPase KRas

K07828

NRAS; GTPase NRas

K08026

ONECUT1, HNF6; one cut domain, family member 1 (hepatocyte nuclear factor 6)

K08031

PAX6; paired box protein 6

K08553

NR3B2, ESRRB; estrogen-related receptor beta

K09063

TCF3, E2A; transcription factor E2-alpha

K09071

HAND1; heart-and neural crest derivatives-expressed protein 1

K09081

NEUROG1; neurogenin 1

K09222

REST; RE1-silencing transcription factor

K09301

HOX_1; homeobox protein HoxA/B/D1

K09326

OTX1; homeobox protein OTX1

K09354

HESX1; homeobox protein expressed in ES cells 1

K09367

POU5F; POU domain transcription factor, class 5

K09370

ISL1; insulin gene enhancer protein ISL-1

K09378

ZFHX3, ATBF1; zinc finger homeobox protein 3

K10164

NANOG; homeobox protein Nanog

K10177

TBX3; T-box protein 3

K11138

RIF1; telomere-associated protein RIF1

K11217

JAK1; Janus kinase 1 [EC:2.7.10.2]

K11218

JAK3; Janus kinase 3 [EC:2.7.10.2]

K11305

MYST3, KAT6A; histone acetyltransferase MYST3 [EC:2.3.1.48]

K11421

SETDB1; [histone H3]-N6,N6-dimethyl-lysine9 N-methyltransferase [EC:2.1.1.366]

K11459

PCGF4, BMI1; polycomb group RING finger protein 4

K11460

PCGF2, RNF110; polycomb group RING finger protein 2

K11470

PCGF6, MBLR; polycomb group RING finger protein 6

K11478

JARID2, JMJ; protein Jumonji

K11487

PCGF1, NSPC1; polycomb group RING finger protein 1

K11488

PCGF3; polycomb group RING finger protein 3

K11489

PCGF5; polycomb group RING finger protein 5

K13567

ACVR1B, ALK4; activin receptor type-1B [EC:2.7.11.30]

K13568

ACVR1C, ALK7; activin receptor type-1C [EC:2.7.11.30]

K13578

BMPR1B, ALK6, CDw293; bone morphogenetic protein receptor type-1B [EC:2.7.11.30]

K13596

ACVR2B; activin receptor type-2B [EC:2.7.11.30]

K14439

SMARCAD1; SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily A containing DEAD/H box 1 [EC:5.6.2.-]

K15613

MEIS1; homeobox protein Meis1

K16790

SMAD5; mothers against decapentaplegic homolog 5

K16791

SMAD9, SMAD8; mothers against decapentaplegic homolog 9

K16796

SOX2; transcription factor SOX2 (SOX group B)

K17693

ID2; DNA-binding protein inhibitor ID2

K17694

ID3; DNA-binding protein inhibitor ID3

K17695

ID4; DNA-binding protein inhibitor ID4

K17846

KLF4; krueppel-like factor 4

K18484

MYF5; myogenic factor 5

K18487

ZIC3; zinc finger protein ZIC 3

K18489

DLX5; homeobox protein DLX5

K18491

ESX1; homeobox protein ESX1

K18493

LHX5; LIM homeobox protein 5

K18497

FGF2; fibroblast growth factor 2

K18498

DUSP9, MKP4; dual specificity phosphatase 9 [EC:3.1.3.16 3.1.3.48]

K18499

SKIL; Ski-like protein

K22687

INHBB; inhibin beta B chain

K22688

INHBC; inhibin beta C chain

K22689

INHBE; inhibin beta E chain

K23605

SMAD3; mothers against decapentaplegic homolog 3

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