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KEGG   PATHWAY: hsa04550
hsa04550                    Pathway                                
Signaling pathways regulating pluripotency of stem cells - Homo sapiens (human)
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
Pathway map
hsa04550  Signaling pathways regulating pluripotency of stem cells

D05338  Palifermin (USAN/INN)
D05716  Repifermin (USAN/INN)
D10889  Momelotinib hydrochloride hydrate (JAN)
D10903  Amcasertib (USAN/INN)
D11701  Luspatercept (USAN/INN)
D11889  Unesblin (USAN)
D12547  Zilurgisertib (USAN/INN)
D12548  Zilurgisertib fumarate (USAN)
Other DBs
GO: 2000036
Homo sapiens (human) [GN:hsa]
3976  LIF; LIF interleukin 6 family cytokine [KO:K05419]
3977  LIFR; LIF receptor subunit alpha [KO:K05058]
3572  IL6ST; interleukin 6 cytokine family signal transducer [KO:K05060]
3716  JAK1; Janus kinase 1 [KO:K11217] [EC:]
3717  JAK2; Janus kinase 2 [KO:K04447] [EC:]
3718  JAK3; Janus kinase 3 [KO:K11218] [EC:]
6774  STAT3; signal transducer and activator of transcription 3 [KO:K04692]
9314  KLF4; KLF transcription factor 4 [KO:K17846]
6657  SOX2; SRY-box transcription factor 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:]
5605  MAP2K2; mitogen-activated protein kinase kinase 2 [KO:K04369] [EC:]
5594  MAPK1; mitogen-activated protein kinase 1 [KO:K04371] [EC:]
5595  MAPK3; mitogen-activated protein kinase 3 [KO:K04371] [EC:]
5290  PIK3CA; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha [KO:K00922] [EC:]
5293  PIK3CD; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta [KO:K00922] [EC:]
5291  PIK3CB; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta [KO:K00922] [EC:]
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:]
208  AKT2; AKT serine/threonine kinase 2 [KO:K04456] [EC:]
10000  AKT3; AKT serine/threonine kinase 3 [KO:K04456] [EC:]
6926  TBX3; T-box transcription factor 3 [KO:K10177]
79923  NANOG; Nanog homeobox [KO:K10164]
388112  NANOGP8; Nanog homeobox retrogene P8 [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:]
130399  ACVR1C; activin A receptor type 1C [KO:K13568] [EC:]
92  ACVR2A; activin A receptor type 2A [KO:K04670] [EC:]
93  ACVR2B; activin A receptor type 2B [KO:K13596] [EC:]
4087  SMAD2; SMAD family member 2 [KO:K04500]
4088  SMAD3; SMAD family member 3 [KO:K23605]
652  BMP4; bone morphogenetic protein 4 [KO:K04662]
657  BMPR1A; bone morphogenetic protein receptor type 1A [KO:K04673] [EC:]
658  BMPR1B; bone morphogenetic protein receptor type 1B [KO:K13578] [EC:]
90  ACVR1; activin A receptor type 1 [KO:K04675] [EC:]
659  BMPR2; bone morphogenetic protein receptor type 2 [KO:K04671] [EC:]
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 [KO:K04680]
3398  ID2; inhibitor of DNA binding 2 [KO:K17693]
3399  ID3; inhibitor of DNA binding 3 [KO:K17694]
3400  ID4; inhibitor of DNA binding 4 [KO:K17695]
1852  DUSP9; dual specificity phosphatase 9 [KO:K18498] [EC:]
5600  MAPK11; mitogen-activated protein kinase 11 [KO:K04441] [EC:]
6300  MAPK12; mitogen-activated protein kinase 12 [KO:K04441] [EC:]
5603  MAPK13; mitogen-activated protein kinase 13 [KO:K04441] [EC:]
1432  MAPK14; mitogen-activated protein kinase 14 [KO:K04441] [EC:]
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:]
8312  AXIN1; axin 1 [KO:K02157]
8313  AXIN2; axin 2 [KO:K04385]
324  APC; APC regulator of WNT signaling pathway [KO:K02085]
10297  APC2; APC regulator of WNT signaling pathway 2 [KO:K02085]
1499  CTNNB1; catenin beta 1 [KO:K02105]
6929  TCF3; transcription factor 3 [KO:K09063]
2103  ESRRB; estrogen related receptor beta [KO:K08553]
6932  TCF7; transcription factor 7 [KO:K02620]
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:]
2263  FGFR2; fibroblast growth factor receptor 2 [KO:K05093] [EC:]
2261  FGFR3; fibroblast growth factor receptor 3 [KO:K05094] [EC:]
2264  FGFR4; fibroblast growth factor receptor 4 [KO:K05095] [EC:]
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:]
3479  IGF1; insulin like growth factor 1 [KO:K05459]
3480  IGF1R; insulin like growth factor 1 receptor [KO:K05087] [EC:]
8820  HESX1; HESX homeobox 1 [KO:K09354]
7547  ZIC3; Zic family member 3 [KO:K18487]
10637  LEFTY1; left-right determination factor 1 [KO:K04668]
7044  LEFTY2; left-right determination factor 2 [KO:K04668]
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:5.6.2.-]
7994  KAT6A; lysine acetyltransferase 6A [KO:K11305] [EC:]
9869  SETDB1; SET domain bifurcated histone lysine methyltransferase 1 [KO:K11421] [EC:]
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]
3211  HOXB1; homeobox B1 [KO:K09301]
3198  HOXA1; homeobox A1 [KO:K09301]
3231  HOXD1; homeobox D1 [KO:K09301]
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]
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)
hsa04010  MAPK signaling pathway
hsa04151  PI3K-Akt signaling pathway
hsa04310  Wnt signaling pathway
hsa04350  TGF-beta signaling pathway
hsa04630  JAK-STAT signaling pathway
KO pathway

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