KEGG   PATHWAY: hsa04550Help
Entry
hsa04550                    Pathway                                

Name
Signaling pathways regulating pluripotency of stem cells - Homo sapiens (human)
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
BRITE hierarchy
Pathway map
hsa04550  Signaling pathways regulating pluripotency of stem cells
hsa04550

Ortholog table
Module
hsa_M00679  BMP signaling [PATH:hsa04550]
hsa_M00681  Activin signaling [PATH:hsa04550]
Disease
H01481  Myelodysplastic syndrome
H02151  Hereditary congenital facial paresis
Drug
D05338  Palifermin (USAN/INN)
D10903  Amcasertib (USAN/INN)
Other DBs
BSID: 1026136
GO: 2000036
Organism
Homo sapiens (human) [GN:hsa]
Gene
3976  LIF; LIF, interleukin 6 family cytokine [KO:K05419]
3977  LIFR; LIF receptor alpha [KO:K05058]
3572  IL6ST; interleukin 6 signal transducer [KO:K05060]
3716  JAK1; Janus kinase 1 [KO:K11217] [EC:2.7.10.2]
3717  JAK2; Janus kinase 2 [KO:K04447] [EC:2.7.10.2]
3718  JAK3; Janus kinase 3 [KO:K11218] [EC:2.7.10.2]
6774  STAT3; signal transducer and activator of transcription 3 [KO:K04692]
9314  KLF4; Kruppel like factor 4 [KO:K17846]
6657  SOX2; SRY-box 2 [KO:K16796]
4609  MYC; MYC proto-oncogene, bHLH transcription factor [KO:K04377]
2885  GRB2; growth factor receptor bound protein 2 [KO:K04364]
5604  MAP2K1; mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:2.7.12.2]
5605  MAP2K2; mitogen-activated protein kinase kinase 2 [KO:K04369] [EC:2.7.12.2]
5594  MAPK1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
5595  MAPK3; mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
5290  PIK3CA; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha [KO:K00922] [EC:2.7.1.153]
5293  PIK3CD; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta [KO:K00922] [EC:2.7.1.153]
5291  PIK3CB; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta [KO:K00922] [EC:2.7.1.153]
5295  PIK3R1; phosphoinositide-3-kinase regulatory subunit 1 [KO:K02649]
5296  PIK3R2; phosphoinositide-3-kinase regulatory subunit 2 [KO:K02649]
8503  PIK3R3; phosphoinositide-3-kinase regulatory subunit 3 [KO:K02649]
207  AKT1; AKT serine/threonine kinase 1 [KO:K04456] [EC:2.7.11.1]
208  AKT2; AKT serine/threonine kinase 2 [KO:K04456] [EC:2.7.11.1]
10000  AKT3; AKT serine/threonine kinase 3 [KO:K04456] [EC:2.7.11.1]
6926  TBX3; T-box 3 [KO:K10177]
79923  NANOG; Nanog homeobox [KO:K10164]
3624  INHBA; inhibin subunit beta A [KO:K04667]
3625  INHBB; inhibin subunit beta B [KO:K22687]
3626  INHBC; inhibin subunit beta C [KO:K22688]
83729  INHBE; inhibin subunit beta E [KO:K22689]
4838  NODAL; nodal growth differentiation factor [KO:K04666]
91  ACVR1B; activin A receptor type 1B [KO:K13567] [EC:2.7.11.30]
130399  ACVR1C; activin A receptor type 1C [KO:K13568] [EC:2.7.11.30]
92  ACVR2A; activin A receptor type 2A [KO:K04670] [EC:2.7.11.30]
93  ACVR2B; activin A receptor type 2B [KO:K13596] [EC:2.7.11.30]
4087  SMAD2; SMAD family member 2 [KO:K04500]
4088  SMAD3; SMAD family member 3 [KO:K04500]
652  BMP4; bone morphogenetic protein 4 [KO:K04662]
657  BMPR1A; bone morphogenetic protein receptor type 1A [KO:K04673] [EC:2.7.11.30]
658  BMPR1B; bone morphogenetic protein receptor type 1B [KO:K13578] [EC:2.7.11.30]
90  ACVR1; activin A receptor type 1 [KO:K04675] [EC:2.7.11.30]
659  BMPR2; bone morphogenetic protein receptor type 2 [KO:K04671] [EC:2.7.11.30]
4086  SMAD1; SMAD family member 1 [KO:K04676]
4090  SMAD5; SMAD family member 5 [KO:K16790]
4093  SMAD9; SMAD family member 9 [KO:K16791]
4089  SMAD4; SMAD family member 4 [KO:K04501]
3397  ID1; inhibitor of DNA binding 1, HLH protein [KO:K04680]
3398  ID2; inhibitor of DNA binding 2 [KO:K17693]
3399  ID3; inhibitor of DNA binding 3, HLH protein [KO:K17694]
3400  ID4; inhibitor of DNA binding 4, HLH protein [KO:K17695]
1852  DUSP9; dual specificity phosphatase 9 [KO:K18498] [EC:3.1.3.48 3.1.3.16]
5600  MAPK11; mitogen-activated protein kinase 11 [KO:K04441] [EC:2.7.11.24]
6300  MAPK12; mitogen-activated protein kinase 12 [KO:K04441] [EC:2.7.11.24]
5603  MAPK13; mitogen-activated protein kinase 13 [KO:K04441] [EC:2.7.11.24]
1432  MAPK14; mitogen-activated protein kinase 14 [KO:K04441] [EC:2.7.11.24]
7471  WNT1; Wnt family member 1 [KO:K03209]
7472  WNT2; Wnt family member 2 [KO:K00182]
7482  WNT2B; Wnt family member 2B [KO:K00182]
7473  WNT3; Wnt family member 3 [KO:K00312]
89780  WNT3A; Wnt family member 3A [KO:K00312]
54361  WNT4; Wnt family member 4 [KO:K00408]
7474  WNT5A; Wnt family member 5A [KO:K00444]
81029  WNT5B; Wnt family member 5B [KO:K00444]
7475  WNT6; Wnt family member 6 [KO:K00445]
7476  WNT7A; Wnt family member 7A [KO:K00572]
7477  WNT7B; Wnt family member 7B [KO:K00572]
7478  WNT8A; Wnt family member 8A [KO:K00714]
7479  WNT8B; Wnt family member 8B [KO:K00714]
7483  WNT9A; Wnt family member 9A [KO:K01064]
7484  WNT9B; Wnt family member 9B [KO:K01064]
7480  WNT10B; Wnt family member 10B [KO:K01357]
80326  WNT10A; Wnt family member 10A [KO:K01357]
7481  WNT11; Wnt family member 11 [KO:K01384]
51384  WNT16; Wnt family member 16 [KO:K01558]
8321  FZD1; frizzled class receptor 1 [KO:K02432]
8324  FZD7; frizzled class receptor 7 [KO:K02432]
2535  FZD2; frizzled class receptor 2 [KO:K02235]
7976  FZD3; frizzled class receptor 3 [KO:K02329]
8322  FZD4; frizzled class receptor 4 [KO:K02354]
7855  FZD5; frizzled class receptor 5 [KO:K02375]
8325  FZD8; frizzled class receptor 8 [KO:K02375]
8323  FZD6; frizzled class receptor 6 [KO:K02376]
11211  FZD10; frizzled class receptor 10 [KO:K02842]
8326  FZD9; frizzled class receptor 9 [KO:K02842]
1857  DVL3; dishevelled segment polarity protein 3 [KO:K02353]
1856  DVL2; dishevelled segment polarity protein 2 [KO:K02353]
1855  DVL1; dishevelled segment polarity protein 1 [KO:K02353]
2932  GSK3B; glycogen synthase kinase 3 beta [KO:K03083] [EC:2.7.11.26]
8312  AXIN1; axin 1 [KO:K02157]
8313  AXIN2; axin 2 [KO:K04385]
324  APC; APC, WNT signaling pathway regulator [KO:K02085]
10297  APC2; APC2, WNT signaling pathway regulator [KO:K02085]
1499  CTNNB1; catenin beta 1 [KO:K02105]
6929  TCF3; transcription factor 3 [KO:K09063]
2103  ESRRB; estrogen related receptor beta [KO:K08553]
6927  HNF1A; HNF1 homeobox A [KO:K08036]
5460  POU5F1; POU class 5 homeobox 1 [KO:K09367]
5462  POU5F1B; POU class 5 homeobox 1B [KO:K09367]
2247  FGF2; fibroblast growth factor 2 [KO:K18497]
2260  FGFR1; fibroblast growth factor receptor 1 [KO:K04362] [EC:2.7.10.1]
2263  FGFR2; fibroblast growth factor receptor 2 [KO:K05093] [EC:2.7.10.1]
2261  FGFR3; fibroblast growth factor receptor 3 [KO:K05094] [EC:2.7.10.1]
2264  FGFR4; fibroblast growth factor receptor 4 [KO:K05095] [EC:2.7.10.1]
3265  HRAS; HRas proto-oncogene, GTPase [KO:K02833]
3845  KRAS; KRAS proto-oncogene, GTPase [KO:K07827]
4893  NRAS; NRAS proto-oncogene, GTPase [KO:K07828]
5894  RAF1; Raf-1 proto-oncogene, serine/threonine kinase [KO:K04366] [EC:2.7.11.1]
3479  IGF1; insulin like growth factor 1 [KO:K05459]
3480  IGF1R; insulin like growth factor 1 receptor [KO:K05087] [EC:2.7.10.1]
8820  HESX1; HESX homeobox 1 [KO:K09354]
7547  ZIC3; Zic family member 3 [KO:K18487]
6498  SKIL; SKI like proto-oncogene [KO:K18499]
56916  SMARCAD1; SWI/SNF-related, matrix-associated actin-dependent regulator of chromatin, subfamily a, containing DEAD/H box 1 [KO:K14439] [EC:3.6.4.12]
7994  KAT6A; lysine acetyltransferase 6A [KO:K11305] [EC:2.3.1.48]
9869  SETDB1; SET domain bifurcated 1 [KO:K11421] [EC:2.1.1.43]
3720  JARID2; jumonji and AT-rich interaction domain containing 2 [KO:K11478]
5978  REST; RE1 silencing transcription factor [KO:K09222]
55183  RIF1; replication timing regulatory factor 1 [KO:K11138]
84759  PCGF1; polycomb group ring finger 1 [KO:K11487]
7703  PCGF2; polycomb group ring finger 2 [KO:K11460]
10336  PCGF3; polycomb group ring finger 3 [KO:K11488]
648  BMI1; BMI1 proto-oncogene, polycomb ring finger [KO:K11459]
100532731  COMMD3-BMI1; COMMD3-BMI1 readthrough [KO:K11459]
84333  PCGF5; polycomb group ring finger 5 [KO:K11489]
84108  PCGF6; polycomb group ring finger 6 [KO:K11470]
5080  PAX6; paired box 6 [KO:K08031]
4211  MEIS1; Meis homeobox 1 [KO:K15613]
64211  LHX5; LIM homeobox 5 [KO:K18493]
5013  OTX1; orthodenticle homeobox 1 [KO:K09326]
4762  NEUROG1; neurogenin 1 [KO:K09081]
9421  HAND1; heart and neural crest derivatives expressed 1 [KO:K09071]
1749  DLX5; distal-less homeobox 5 [KO:K18489]
4617  MYF5; myogenic factor 5 [KO:K18484]
3175  ONECUT1; one cut homeobox 1 [KO:K08026]
3670  ISL1; ISL LIM homeobox 1 [KO:K09370]
463  ZFHX3; zinc finger homeobox 3 [KO:K09378]
80712  ESX1; ESX homeobox 1 [KO:K18491]
3211  HOXB1; homeobox B1 [KO:K09301]
7044  LEFTY2; left-right determination factor 2 [KO:K04668]
Reference
  Authors
Bhartiya D, Lenka N (ed).
  Title
Pluripotent Stem Cells
  Journal
InTech (2013)
DOI:10.5772/45917
Reference
  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
  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
  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
  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
  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
  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
  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
  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
  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
  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
  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
  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
  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
  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
  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
  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
  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
  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
  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
Reference
  Authors
Greenow K, Clarke AR
  Title
Controlling the stem cell compartment and regeneration in vivo: the role of pluripotency pathways.
  Journal
Physiol Rev 92:75-99 (2012)
DOI:10.1152/physrev.00040.2010
KO pathway
ko04550   

DBGET integrated database retrieval system