Myogenesis (Homo sapiens)

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2, 5, 10-121, 684, 93, 7nucleoplasmcytosolBOC-1 TCF12 CDON ABL1CDON p-T180,Y182-MAPK14 CDH4 CDC42 CTNNA1 CTNNB1 MAPK12 CDO:BOCNTN3 ABL1:JLP:CDO complexMYOG CTNNA2 CDH2 BOC-1 Cadherin-catenin:JLP:CDO:BOC:Bnip2-Cdc42CTNNA2 TCF4 GTP MYOD1 p-T293,T300,T387-MEF2C p38 MAPKalpha/beta/gammap-S139-TCF3 CDH2 ABL1 MAPK14 p-T183,Y185-MAPK12 p-T293,T300,T387-MEF2C CDON CDH4 MAPK11 CDH2 CTNNB1 MEF2D MYF5 CDONBNIP2TCF3CTNNB1 CDO:BOC:Neogenin:Netrin-3MEF2B MAPK12 CDH15 CDH15 CDO:BOC:Trans-cadherin homodimer:cateninMYF6 CTNNA2 CTNNA2 MEF2 proteinsCDON BOC-1 MAPK12 Cadherin-catenin:CDO:BOC:Bnip2Cadherin-catenin:CDO:BOC:Bnip2:CDC42-GTPADPCDC42 phospho p38:phosphoMEF2CDON CDH15 CDH2 CDH15 CDH15 MEF2D CDON BOC-1 CDH15 SPAG9 CDON p-T312,T319-MEF2A GTP SPAG9 BOC-1BOC-1 BNIP2 phospho-p38alpha/beta/gammaMAPKCTNNA1 CTNNA1 CTNNA1 p-S139-TCF3 CTNNA2 CDH4 CTNNA2 p-T180,Y182-MAPK11 phospho-MEF2proteinsABL1 BOC-1 CTNNB1 CTNNA1 BNIP2 pp38alpha/beta/gamma:ABL1:JLP:CDO complexp-S139-TCF3 CTNNA1 p-T180,Y182-MAPK11 CTNNA1 MEF2B GTP BNIP2 CDON ATPCDC42 BNIP2 CDC42:GTPCDH15 BOC-1 CTNNA2 CTNNA2 CDH4 MYF6 CTNNB1 CDH15 CTNNB1 GTP TCF4 NEO1 p-T180,Y182-MAPK14 CTNNB1 CTNNB1 MYOG MYOG BOC-1 MAPK14 p-S139-TCF3CDH4 MYF6 MEF2B CDC42 p-S207,T211-MAP2K6CTNNA1 p38alpha/beta/gamma:ABL1:JLP:CDO complexCDH4 CDH2 MEF2D CDC42 MRFsABL1 MYF5 SPAG9CDC42 CDON CDH2 ADPMyoD:phospho-E:phospho MEF2MEF2C BOC-1 BNIP2 MAPK11 MEF2A CDH2 MAPK12 BNIP2 MYOD1 CDH4 GTP NTN3 CDH4 SPAG9 p-T180,Y182-MAPK14 GTP p-T293,T300,T387-MEF2C TCF12 NEO1 MEF2D TCF12 p-T312,T319-MEF2A MEF2B MYOD1 p-T180,Y182-MAPK11 ATPSPAG9 p-T312,T319-MEF2A CDH2 phospho-E proteinsADPTCF4 ATPMYF5 Trans-cadherinhomodimersNetrin-3:NeogeninMyod:phospho-Eheterodimers


Myogenesis, the formation of muscle tissue, is a complex process involving steps of cell proliferation mediated by growth factor signaling, cell differentiation, reorganization of cells to form myotubes, and cell fusion. Here, one regulatory feature of this process has been annotated, the signaling cascade initiated by CDO (cell-adhesion-molecule-related/downregulated by oncogenes) and associated co-receptors. View original pathway at:Reactome.


Pathway is converted from Reactome ID: 525793
Reactome version: 66
Reactome Author 
Reactome Author: Garapati, Phani Vijay

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Ontology Terms



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  1. Lu M, Krauss RS.; ''N-cadherin ligation, but not Sonic hedgehog binding, initiates Cdo-dependent p38alpha/beta MAPK signaling in skeletal myoblasts.''; PubMed Europe PMC Scholia
  2. Zhao M, New L, Kravchenko VV, Kato Y, Gram H, di Padova F, Olson EN, Ulevitch RJ, Han J.; ''Regulation of the MEF2 family of transcription factors by p38.''; PubMed Europe PMC Scholia
  3. Wood CD, Thornton TM, Sabio G, Davis RA, Rincon M.; ''Nuclear localization of p38 MAPK in response to DNA damage.''; PubMed Europe PMC Scholia
  4. Kang JS, Mulieri PJ, Hu Y, Taliana L, Krauss RS.; ''BOC, an Ig superfamily member, associates with CDO to positively regulate myogenic differentiation.''; PubMed Europe PMC Scholia
  5. Zetser A, Gredinger E, Bengal E.; ''p38 mitogen-activated protein kinase pathway promotes skeletal muscle differentiation. Participation of the Mef2c transcription factor.''; PubMed Europe PMC Scholia
  6. Kang JS, Feinleib JL, Knox S, Ketteringham MA, Krauss RS.; ''Promyogenic members of the Ig and cadherin families associate to positively regulate differentiation.''; PubMed Europe PMC Scholia
  7. Blanco-Aparicio C, Torres J, Pulido R.; ''A novel regulatory mechanism of MAP kinases activation and nuclear translocation mediated by PKA and the PTP-SL tyrosine phosphatase.''; PubMed Europe PMC Scholia
  8. Black BL, Molkentin JD, Olson EN.; ''Multiple roles for the MyoD basic region in transmission of transcriptional activation signals and interaction with MEF2.''; PubMed Europe PMC Scholia
  9. Kang JS, Mulieri PJ, Miller C, Sassoon DA, Krauss RS.; ''CDO, a robo-related cell surface protein that mediates myogenic differentiation.''; PubMed Europe PMC Scholia
  10. Han J, Jiang Y, Li Z, Kravchenko VV, Ulevitch RJ.; ''Activation of the transcription factor MEF2C by the MAP kinase p38 in inflammation.''; PubMed Europe PMC Scholia
  11. Yang SH, Galanis A, Sharrocks AD.; ''Targeting of p38 mitogen-activated protein kinases to MEF2 transcription factors.''; PubMed Europe PMC Scholia
  12. Wu Z, Woodring PJ, Bhakta KS, Tamura K, Wen F, Feramisco JR, Karin M, Wang JY, Puri PL.; ''p38 and extracellular signal-regulated kinases regulate the myogenic program at multiple steps.''; PubMed Europe PMC Scholia


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101209view11:10, 1 November 2018ReactomeTeamreactome version 66
100747view20:35, 31 October 2018ReactomeTeamreactome version 65
100291view19:12, 31 October 2018ReactomeTeamreactome version 64
99837view15:56, 31 October 2018ReactomeTeamreactome version 63
99394view14:33, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
93765view13:34, 16 August 2017ReactomeTeamreactome version 61
93289view11:19, 9 August 2017ReactomeTeamreactome version 61
88022view13:31, 25 July 2016RyanmillerOntology Term : 'regulatory pathway' added !
86374view09:16, 11 July 2016ReactomeTeamreactome version 56
83197view10:21, 18 November 2015ReactomeTeamVersion54
81576view13:06, 21 August 2015ReactomeTeamVersion53
77038view08:33, 17 July 2014ReactomeTeamFixed remaining interactions
76743view12:10, 16 July 2014ReactomeTeamFixed remaining interactions
76068view10:13, 11 June 2014ReactomeTeamRe-fixing comment source
75778view11:29, 10 June 2014ReactomeTeamReactome 48 Update
75128view14:07, 8 May 2014AnweshaFixing comment source for displaying WikiPathways description
74775view08:51, 30 April 2014ReactomeTeamReactome46
44931view10:57, 6 October 2011MartijnVanIerselOntology Term : 'muscle cell' added !
42083view21:55, 4 March 2011MaintBotAutomatic update
39891view05:55, 21 January 2011MaintBotNew pathway

External references


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NameTypeDatabase referenceComment
ABL1 ProteinP00519 (Uniprot-TrEMBL)
ABL1:JLP:CDO complexComplexR-HSA-449191 (Reactome)
ABL1ProteinP00519 (Uniprot-TrEMBL)
ADPMetaboliteCHEBI:16761 (ChEBI)
ATPMetaboliteCHEBI:15422 (ChEBI)
BNIP2 ProteinQ12982 (Uniprot-TrEMBL)
BNIP2ProteinQ12982 (Uniprot-TrEMBL)
BOC-1 ProteinQ9BWV1-1 (Uniprot-TrEMBL)
BOC-1ProteinQ9BWV1-1 (Uniprot-TrEMBL)
CDC42 ProteinP60953 (Uniprot-TrEMBL)
CDC42:GTPComplexR-HSA-182921 (Reactome)
CDH15 ProteinP55291 (Uniprot-TrEMBL)
CDH2 ProteinP19022 (Uniprot-TrEMBL)
CDH4 ProteinP55283 (Uniprot-TrEMBL)
CDO:BOC:Neogenin:Netrin-3ComplexR-HSA-375091 (Reactome)
CDO:BOC:Trans-cadherin homodimer:cateninComplexR-HSA-375092 (Reactome)
CDO:BOCComplexR-HSA-375094 (Reactome)
CDON ProteinQ4KMG0 (Uniprot-TrEMBL)
CDONProteinQ4KMG0 (Uniprot-TrEMBL)
CTNNA1 ProteinP35221 (Uniprot-TrEMBL)
CTNNA2 ProteinP26232 (Uniprot-TrEMBL)
CTNNB1 ProteinP35222 (Uniprot-TrEMBL)
Cadherin-catenin:CDO:BOC:Bnip2:CDC42-GTPComplexR-HSA-448875 (Reactome)
Cadherin-catenin:CDO:BOC:Bnip2ComplexR-HSA-376008 (Reactome)
Cadherin-catenin:JLP:CDO:BOC:Bnip2-Cdc42ComplexR-HSA-376011 (Reactome)
GTP MetaboliteCHEBI:15996 (ChEBI)
MAPK11 ProteinQ15759 (Uniprot-TrEMBL)
MAPK12 ProteinP53778 (Uniprot-TrEMBL)
MAPK14 ProteinQ16539 (Uniprot-TrEMBL)
MEF2 proteinsComplexR-HSA-448868 (Reactome)
MEF2A ProteinQ02078 (Uniprot-TrEMBL)
MEF2B ProteinQ02080 (Uniprot-TrEMBL)
MEF2C ProteinQ06413 (Uniprot-TrEMBL)
MEF2D ProteinQ14814 (Uniprot-TrEMBL)
MRFsComplexR-HSA-448854 (Reactome)
MYF5 ProteinP13349 (Uniprot-TrEMBL)
MYF6 ProteinP23409 (Uniprot-TrEMBL)
MYOD1 ProteinP15172 (Uniprot-TrEMBL)
MYOG ProteinP15173 (Uniprot-TrEMBL)
MyoD:phospho-E:phospho MEF2ComplexR-HSA-448877 (Reactome)
Myod:phospho-E heterodimersComplexR-HSA-448886 (Reactome)
NEO1 ProteinQ92859 (Uniprot-TrEMBL)
NTN3 ProteinO00634 (Uniprot-TrEMBL)
Netrin-3:NeogeninComplexR-HSA-448880 (Reactome)
SPAG9 ProteinO60271 (Uniprot-TrEMBL)
SPAG9ProteinO60271 (Uniprot-TrEMBL)
TCF12 ProteinQ99081 (Uniprot-TrEMBL)
TCF3ProteinP15923 (Uniprot-TrEMBL)
TCF4 ProteinP15884 (Uniprot-TrEMBL)
Trans-cadherin homodimersComplexR-HSA-448888 (Reactome)
p-S139-TCF3 ProteinP15923 (Uniprot-TrEMBL)
p-S139-TCF3ProteinP15923 (Uniprot-TrEMBL)
p-S207,T211-MAP2K6ProteinP52564 (Uniprot-TrEMBL)
p-T180,Y182-MAPK11 ProteinQ15759 (Uniprot-TrEMBL)
p-T180,Y182-MAPK14 ProteinQ16539 (Uniprot-TrEMBL)
p-T183,Y185-MAPK12 ProteinP53778 (Uniprot-TrEMBL)
p-T293,T300,T387-MEF2C ProteinQ06413 (Uniprot-TrEMBL)
p-T312,T319-MEF2A ProteinQ02078 (Uniprot-TrEMBL)
p38 alpha/beta/gamma:ABL1:JLP:CDO complexComplexR-HSA-448887 (Reactome)
p38 MAPK alpha/beta/gammaComplexR-HSA-448855 (Reactome)
phospho p38:phospho MEF2ComplexR-HSA-448874 (Reactome)
phospho-E proteinsComplexR-HSA-448867 (Reactome)
phospho-MEF2 proteinsComplexR-HSA-448866 (Reactome)


ComplexR-HSA-448858 (Reactome)
pp38 alpha/beta/gamma:ABL1:JLP:CDO complexComplexR-HSA-448881 (Reactome)

Annotated Interactions

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SourceTargetTypeDatabase referenceComment
ABL1:JLP:CDO complexArrowR-HSA-448958 (Reactome)
ABL1:JLP:CDO complexArrowR-HSA-449200 (Reactome)
ABL1:JLP:CDO complexR-HSA-448957 (Reactome)
ABL1R-HSA-449200 (Reactome)
ADPArrowR-HSA-448948 (Reactome)
ADPArrowR-HSA-448951 (Reactome)
ADPArrowR-HSA-448955 (Reactome)
ATPR-HSA-448948 (Reactome)
ATPR-HSA-448951 (Reactome)
ATPR-HSA-448955 (Reactome)
BNIP2R-HSA-376121 (Reactome)
BOC-1R-HSA-375138 (Reactome)
CDC42:GTPR-HSA-376119 (Reactome)
CDO:BOC:Neogenin:Netrin-3ArrowR-HSA-375141 (Reactome)
CDO:BOC:Trans-cadherin homodimer:cateninArrowR-HSA-375140 (Reactome)
CDO:BOC:Trans-cadherin homodimer:cateninR-HSA-376121 (Reactome)
CDO:BOCArrowR-HSA-375138 (Reactome)
CDO:BOCR-HSA-375140 (Reactome)
CDO:BOCR-HSA-375141 (Reactome)
CDONR-HSA-375138 (Reactome)
Cadherin-catenin:CDO:BOC:Bnip2:CDC42-GTPArrowR-HSA-376119 (Reactome)
Cadherin-catenin:CDO:BOC:Bnip2:CDC42-GTPR-HSA-376117 (Reactome)
Cadherin-catenin:CDO:BOC:Bnip2ArrowR-HSA-376121 (Reactome)
Cadherin-catenin:CDO:BOC:Bnip2R-HSA-376119 (Reactome)
Cadherin-catenin:JLP:CDO:BOC:Bnip2-Cdc42ArrowR-HSA-376117 (Reactome)
Cadherin-catenin:JLP:CDO:BOC:Bnip2-Cdc42R-HSA-449200 (Reactome)
MEF2 proteinsR-HSA-448955 (Reactome)
MRFsR-HSA-448962 (Reactome)
MyoD:phospho-E:phospho MEF2ArrowR-HSA-448963 (Reactome)
Myod:phospho-E heterodimersArrowR-HSA-448962 (Reactome)
Myod:phospho-E heterodimersR-HSA-448963 (Reactome)
Netrin-3:NeogeninR-HSA-375141 (Reactome)
R-HSA-375138 (Reactome) CDO and BOC form complexes in a cis fashion via association of both their ectodomains and their intracellular domains. CDO and BOC exert their effects as components of a receptor, in which the role of BOC is primarily extracellular and that of CDO includes intracellular signaling.
R-HSA-375140 (Reactome) In myoblasts, CDO forms cis complexes with the cell–cell adhesion molecule N-cadherin, which is itself involved in regulation of myogenesis. These cadherin complexes contain beta- and alpha-catenins which are important for N-cadherin's effect in myoblast. When CDO binds with ligated cadherins, its intracellular region undergoes a change in conformation and/or posttranslational modi?cation that permits its stable association with Bnip-2 and JLP and, consequently, activation of p38.
R-HSA-375141 (Reactome) CDO selectively binds to neogenin in a cis fashion and this interaction involves extracellular domains of both proteins. CDO is essential in mediating netrin-3-induced differentiation of myoblasts by neogenin. Neogenin and netrin-3 stimulate myotube formation and enhance myogenic bHLH-and NFAT-dependent transcription.
R-HSA-376117 (Reactome) JLP is a scaffold protein for the p38 MAPK pathway. During myogenic differentiation JLP binds the intracellular region of CDO which in turn binds p38 leading to p38 activation. The major CDO-binding region of JLP resides between amino acids 465-647.
R-HSA-376119 (Reactome) Bnip-2 interacts with Cdc42 through its Bnip-2 and Cdc42GAP homology (BCH) domain and thus it acts as a linkage between the CDO receptor and the Cdc42 activity. Formation of a CDO-Bnip-2-Cdc42 complex stimulates Cdc42 activation which in turn promotes p38 alpha/beta activity and cell differentiation.
R-HSA-376121 (Reactome) Bnip-2 is a scaffold protein with a single recognizable motif, a BCH domain that spans its C-terminal half involved in the dynamic regulation of Cdc42 signaling. The CDO intracellular region binds Bnip-2 and this complex regulates Cdc42 activity.
R-HSA-448948 (Reactome) p38 MAPK plays a fundamental role in the transition of myoblasts to different myocytes. Activated p38 MAPK phosphorylates E12/E47, a member of the E protein subfamily of bHLH proteins. p38 MAPK in particular phosphorylates Ser140 of E47. Its been observed that phosphorylation of E47 improves its ability to form heterodimers with Myod transcription factor.
R-HSA-448951 (Reactome) p38 alpha/beta MAPK is well established as a promyogenic kinase, but the mechanism by which it is activated during differentiation is not well understood. CDO, JLP and p38 form a ternary complex and it is anticipated that in its role as a scaffold, JLP brings additional components of the pathway, such as MKKs, to these complexes and cooperate to activate p38 alpha/beta MAPK pathway. p38 is activated by phosphorylation on a canonical TxY motif by dual specificity kinases MKK6 and MKK3. MKK6 is the most abundant in skeletal muscles and displays minimal substrate selectivity among all p38 isoforms.
R-HSA-448955 (Reactome) The family of transcription factors myocyte enhancer factor-2 (MEF2) regulate myogenesis through combinatorial interactions with other transcription factors to the MEF2 site found in the promoter regions of numerous muscle specific genes. There are four members of the MEF2 family, MEF2A to D.
p38 MAPK plays a role in the regulation of the MEF2 family members and this is mediated by the phosphorylation of two or three (Thr312 and 319 in MEF2A and Thr 293, 300 and ser387 in MEF2C) amino acids in the C-terminal activation domain of MEF2 factors. MEF2A and MEF2C are preferred substrates for p38 compared with MEF2B and MEF2D. The phosphorylation of MEF2 members results in their increased transcriptional activity.
R-HSA-448957 (Reactome) JLP is a p38 alpha/beta MAPK scaffold protein. p38 alpha/beta MAPK binds to two sites within JLP (amino acids 1-110 and 160-209), neither of which overlaps the CDO binding region.
R-HSA-448958 (Reactome) p38 MAPK is activated by phosphorylation in response to CDO-BOC interactions. Activated p38 MAPK may translocate into the nucleus to further activate myogenic related transcription factors.
R-HSA-448962 (Reactome) MyoD is a basic helix loop helix (bHLH) myoblast specific transcription factor defined as a 'master switch' gene in that it can convert other cell types into muscles if the gene is active in them. bHLH proteins Myf5, Myogenin and MRF4/Myf6 are highly related to MyoD and these along with MyoD form the 'MyoD family' of transcription factors, also called the myogenic regulatory factors (MRFs).
MRFs form transcriptionally active heterodimers with the widely expressed E proteins, a distinct group of bHLH proteins including E12/E47, ITF-2 and HEB. Dimerization of these proteins juxtaposes their basic domains forming a functional DNA binding domain. MyoD/E protein heterodimers preferentially bind the DNA consensus sequence referred to as an E-box (CANNTG) in the control regions of muscle-specific genes and activate gene transcription of genes that are expressed in skeletal muscle.
R-HSA-448963 (Reactome) MyoD-E protein heterodimers interact with MEF2 proteins to synergistically activate myogenesis. This interaction occurs via association of these two heterologous classes of transcription factors through their DNA-binding and dimerization motifs. The combinatorial associations of these two protein families appear to establish a transcriptional code specific for skeletal muscle gene activation. Together with the Mef2 proteins and E proteins, MyoD transcription factors are responsible for coordinating muscle-specific gene expression in the undifferentiated myoblast. MyoD activation leads to expression of myogenin, M-cadherin, myosin heavy and light chains, and muscle creatine kinase.
R-HSA-449200 (Reactome) ABL binds to the cytoplasmic tail of CDO and also to the p38 MAPK scaffold protein JLP. ABL binds a proline-rich motif in CDO via its SH3 domain, and ABL is necessary for full activation of p38 MAPK, during myogenic differentiation.
SPAG9R-HSA-376117 (Reactome)
TCF3R-HSA-448948 (Reactome)
Trans-cadherin homodimersR-HSA-375140 (Reactome)
p-S139-TCF3ArrowR-HSA-448948 (Reactome)
p-S207,T211-MAP2K6mim-catalysisR-HSA-448951 (Reactome)
p38 alpha/beta/gamma:ABL1:JLP:CDO complexArrowR-HSA-448957 (Reactome)
p38 alpha/beta/gamma:ABL1:JLP:CDO complexR-HSA-448951 (Reactome)
p38 MAPK alpha/beta/gammaR-HSA-448957 (Reactome)
phospho p38:phospho MEF2ArrowR-HSA-448955 (Reactome)
phospho-E proteinsR-HSA-448962 (Reactome)
phospho-MEF2 proteinsR-HSA-448963 (Reactome)


ArrowR-HSA-448958 (Reactome)


R-HSA-448955 (Reactome)


mim-catalysisR-HSA-448948 (Reactome)


mim-catalysisR-HSA-448955 (Reactome)
pp38 alpha/beta/gamma:ABL1:JLP:CDO complexArrowR-HSA-448951 (Reactome)
pp38 alpha/beta/gamma:ABL1:JLP:CDO complexR-HSA-448958 (Reactome)
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