The influence of laminopathies on Wnt signaling (Homo sapiens)

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25231, 1018181610191216+ feedbackHuman MSCAdipogenic StimuliAdipocytesPreadipocytesPreadipogenic genesWnt target genesAdipocyte genesImpaired expansion/ differentiationof WAT24MyoblastOsteoblastAdiponectinMIRLET7BCCND1SLC2A45Wnt SignalingWnt SignalingPPAR-γCEBPDCEBPB3CEBPA23WNT10B2226S Proteasome Degredation7, 20GSK3BCSNK1A1CTNNB1CSNK1A1LAPCAXIN1CTNNB1CTNNB1LEF1TCF7TCF7L2TCF7L1CTNNB1aaXNull mutationsCaaX group15 amino acidsZMPSTE24Prelamin-ALMNAIsoprenylcysteine carboxyl methyltransferase CFarnesyltransferasePrelamin-ACaaX groupPrelamin-APrelamin-ACZMPSTE24CMature lamin ACo-localisationSREBP1cMIR33B618Prelamin-APrelamin-A15SREBP1cPPARG11, 14SREBP SignalingRestrictive Dermopathy2, 8Truncated Prelamin-A9, 17RISC complexCDK6AGO2TARBP2HMGA2DICER14MIR33BSPP1RUNX2TLE1Hutchinson-Gilford Progeria SyndromeHES1HES5ProgerinNotch SignalingHigh Bone TurnoverEMDEmerinCTNNB1EmerinFamilial Partial LIpodystrophyCH3Process with unknown interacting molecules PhosphateUbiquitinFarnesyl GroupLaminopathic signalingEmerin13TOR1AIP1Mature lamin A


Description

The current pathway represents the different molecular interactions that may occur following the dis-regulation of signaling pathways involved in adipocyte differentiation and proliferation which may result in the abnormal distribution of white adipose tissue, leading to the onset of lipodystrophic syndromes. This laminopathic pathway stems from mutations mainly occuring in the LMNA gene can be associated with the onset of other laminopathic syndromes due to a malfunction in the lamin A processing pathway.Other laminopathic diseases are associated with LMNA mutations, thus this pathway represents the overlapping interactions involved in such phenotypic diseases.

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Ontology Terms

 

Bibliography

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  1. Voronkov, A, Krauss, S; ''Wnt/beta-Catenin Signaling and Small Molecule Inhibitors''; Current Pharmaceutical Design,19, 634-664, 2013
  2. Wang, X, Sato, R, Brown, M. S, Hua, X, Goldstein, J.L; ''SREBP-1, a membrane-bound transcription factor released by sterol-regulated proteolysis''; Cell, 77(1), 53-62, 1994
  3. Ramji, D. P, Foka, P; ''CCAAT/enhancer-binding proteins: structure, function and regulation''; Biochem. J, 365, 561–575, 2002
  4. Pratt AJ, MacRae IJ; ''The RNA-induced silencing complex: a versatile gene-silencing machine.''; J Biol Chem, 2009 PubMed Europe PMC
  5. Sun, T, Fu, M, Bookout, A. L, Kliewer, S. A, Mangelsdorf, D. J; ''MicroRNA let-7 Regulates 3T3-L1 Adipogenesis''; Molecular Endocrinology, 23(6),925–931, 2009
  6. Lloyd, D.J, Trembath, R.C, Shackleton, S; ''A novel interaction between lamin A and SREBP1: implications for partial lipodystrophy and other laminopathies''; Human Molecular Genetics, 11(7), 769–777, 2002
  7. Aberle H, Bauer A, Stappert J, Kispert A, Kemler R; ''beta-catenin is a target for the ubiquitin-proteasome pathway.''; EMBO J, 1997 PubMed Europe PMC
  8. Wang, X, Sato, R, Brown, M. S, Hua, X, Goldstein, J.L; ''SREBP-1, a membrane-bound transcription factor released by sterol-regulated proteolysis ''; Cell, 77(1), 53-62, 1994
  9. Navarro, C. L, De Sandre-Giovannoli,A, Bernard, R, Boccaccio, I, Boyer, A, Geneviève, D, Hadj-Rabia, S, Gaudy-Marqueste, C, Smitt, H. S, Vabres, P, Faivre, L, Verloes, A, Van Essen, T, Flori, E, Hennekam, R, Beemer, F.A, Laurent, N, Le Merrer, M, Cau, P, Lévy, N; ''Lamin A and ZMPSTE24 (FACE-1) defects cause nuclear disorganization and identify restrictive dermopathy as a lethal neonatal laminopathy''; Human Molecular Genetics,13(20), 2493–2503,, 2004
  10. Voronkov, A, Krauss, S; ''Wnt/beta-Catenin Signaling and Small Molecule Inhibitors''; Current Pharmaceutical Design,19, 634-664, 2013
  11. Hegele, R. A, Cao, H, Frankowski, C, Mathews, S. T, Leff, T; ''PPARG F388L, a Transactivation-Deficient Mutant, in Familial Partial Lipodystrophy''; Diabetes, 51(12): 3586-3590., 2002
  12. Ross, S. E, Hemati, N, Longo, K. A, Bennett, C. B, Lucas, P. C, Erickson, R. L, MacDougald, O. A.; ''Inhibition of Adipogenesis by Wnt Signaling''; Science, 289(5481), 950-953, 2000
  13. Clements, L, Manila, S, Love, D. R, Morris, G. E; ''Direct Interaction Between Emerin and Lamin A''; Biochemical and Biophysical Research Communications, 267(3), 709-714, 2000
  14. Hegele, R. A, Cao, H, Frankowski, C, Mathews, S. T, Leff, T; ''PPARG F388L, a Transactivation-Deficient Mutant, in Familial Partial Lipodystrophy ''; Diabetes, 51(12): 3586-3590, 2002
  15. Lloyd, D.J, Trembath, R.C, Shackleton, S; ''A novel interaction between lamin A and SREBP1: implications for partial lipodystrophy and other laminopathies''; Human Molecular Genetics, 11(7), 769–777, 2002
  16. DE BOER, J, WANG, H. J, VAN BLITTERSWIJK,C; ''Effects of Wnt Signaling on Proliferation and Differentiation of Human Mesenchymal Stem Cells''; TISSUE ENGINEERING,10, 3/4, 2004
  17. Navarro, C. L, De Sandre-Giovannoli,A, Bernard, R, Boccaccio, I, Boyer, A, Geneviève, D, Hadj-Rabia, S, Gaudy-Marqueste, C, Smitt, H. S, Vabres, P, Faivre, L, Verloes, A, Van Essen, T, Flori, E, Hennekam, R, Beemer, F.A, Laurent, N, Le Merrer, M, Cau, P, Lévy, N; ''Lamin A and ZMPSTE24 (FACE-1) defects cause nuclear disorganization and identify restrictive dermopathy as a lethal neonatal laminopathy''; Human Molecular Genetics,13(20), 2493–2503, 2004
  18. Price, N. L, Holtrup, B, Kwei, S. L, Wabitsch, M, Rodeheffer, M, Bianchini, L, Suárez, Y, Fernández-Hernando, C; ''SREBP-1c/MicroRNA 33b Genomic Loci Control Adipocyte Differentiation''; Molecular and Cellular Biology, 36(7), 2016
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  21. Sinensky, M, Fantle, K, Trujillo, M, McLain, T, Kupfer, A, Dalton, M; ''The processing pathway of prelamin A''; Journal of Cell Science 107, 61-67, 1994
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  24. Guo, L. G, Li, X, Tang, Q. Q; ''Transcriptional Regulation of Adipocyte Differentiation: A Central Role for CCAAT/Enhancer-binding Protein (C/EBP) β''; The Journal of Biological Chemistry 290, 755-761, 2014
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History

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CompareRevisionActionTimeUserComment
109506view12:40, 20 March 2020FehrhartOntology Term : 'progeria' added !
109484view11:38, 19 March 2020L DupuisConverted interaction lines to graphical lines in legend
109449view09:17, 18 March 2020ZoebaroisAdded the appropriate origins of the interacting arrows and included the WikiPathways identifier to the second Wnt Signaling pathway
109436view10:58, 17 March 2020ZoebaroisModified title
109325view13:29, 13 March 2020ZoebaroisOntology Term : 'disease pathway' added !
109324view12:42, 13 March 2020ZoebaroisModified description
109323view12:34, 13 March 2020ZoebaroisNew pathway

External references

DataNodes

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NameTypeDatabase referenceComment
AGO2GeneProduct27161 (Entrez Gene)
APCGeneProduct324 (Entrez Gene)
AXIN1GeneProduct8312 (Entrez Gene)
AdiponectinProteinQ15848 (Uniprot-TrEMBL) glucose regulation and fatty acid oxidation metabolism --> is secreated from adipose tissue
CMetaboliteCHEBI:4052 (ChEBI)
CCND1GeneProduct595 (Entrez Gene)
CDK6GeneProduct1021 (Entrez Gene)
CEBPAGeneProduct1050 (Entrez Gene) is down regulated following overexpression of miR33B
CEBPBGeneProduct1051 (Entrez Gene)
  • activated in early stages of adipogenesis --> activates transcription of PPARG and CEBPA by binding to promoter region in later stages of adipogenesis as are anti mitotic- promote terminal differentiation
  • Type your comment here
CEBPDGeneProduct1052 (Entrez Gene)
CSNK1A1GeneProduct1452 (Entrez Gene)
CSNK1A1LGeneProduct122011 (Entrez Gene)
CTNNB1GeneProduct1499 (Entrez Gene)
DICER1GeneProduct23405 (Entrez Gene)
EMDGeneProduct2010 (Entrez Gene) Mutations are linked to X-EMD
EmerinProteinF8WEQ1 (Uniprot-TrEMBL)
FarnesyltransferaseGeneProduct2339 (Entrez Gene)
GSK3BGeneProduct2932 (Entrez Gene)
HES1GeneProduct3280 (Entrez Gene)
HES5GeneProduct388585 (Entrez Gene)
HMGA2GeneProduct8091 (Entrez Gene)
  • chromatin remodeling factor--> important role in the clonal-expansion phase of adipogenesis - may be able to control critical genes involved in cellular proliferation--> loss of HMGA2 impairs adipocyte differentiation
  • overexpression of miR33B caused a significant reduction in HMGA2
  • HMGA2 is induced during the clonal-expansion phase of adipogenesis but reduced following terminal differentiation
  • Type your comment here
Hutchinson-Gilford Progeria SyndromePathwayWP4320 (WikiPathways)
Isoprenylcysteine carboxyl methyltransferase GeneProduct23463 (Entrez Gene)
LEF1GeneProduct51176 (Entrez Gene)
LMNAGeneProduct4000 (Entrez Gene) Single point mutations = AD-EMD
MIR33BGeneProduct693120 (Entrez Gene)
MIRLET7BGeneProduct406884 (Entrez Gene) targets HMGA2, decreasing it --> high amounts in mature adipocytes
Mature lamin AGeneProduct4000 (Entrez Gene)
Notch SignalingPathwayWP268 (WikiPathways)
PPAR-γGeneProduct5468 (Entrez Gene) is down regulated following overexpression of miR33B
PPARGGeneProduct5468 (Entrez Gene) Novel F388L mutation is associated with a form of partial lipodystrophy
Prelamin-AProteinD6RB20 (Uniprot-TrEMBL)
ProgerinGeneProduct4000 (Entrez Gene)
RUNX2GeneProduct860 (Entrez Gene)
SLC2A4GeneProduct6517 (Entrez Gene) GLUT4- associated with noninsulin diabetes mellitus
SPP1GeneProduct6696 (Entrez Gene)
SREBP SignalingPathwayWP1982 (WikiPathways)
SREBP1cGeneProduct6720 (Entrez Gene)
TARBP2GeneProduct6895 (Entrez Gene)
TCF7GeneProduct6932 (Entrez Gene)
TCF7L1GeneProduct83439 (Entrez Gene)
TCF7L2GeneProduct6934 (Entrez Gene)
TLE1GeneProduct7088 (Entrez Gene)
TOR1AIP1GeneProduct26092 (Entrez Gene)
Truncated Prelamin-AProteinD6RB20 (Uniprot-TrEMBL)
  • LMNA heterozygous splicing mutation --> loss of exon 11 results in a truncated pre lamin A - removal of Carboxyl terminal motif - interaction with other proteins - disrupted function
  • can also result from ZMPSTE24 mutations - premature stop codon - no propper processing of lamin A - can also result from null mutations
WNT10BGeneProduct7480 (Entrez Gene) upregulation will stimulate wnt signaling to down regulate adipogenesis
Wnt SignalingPathwayWP428 (WikiPathways)
  • Wnt signaling inhibits protease complex to allow for beta catenin localisation into the nucleus and prevent its degredation
  • Wnt signaling functions as an adipogenic switch. When it is on, adipogenesis is repressed --> in first days of adipogenesis- differentiation is blocked

    when it is off, adipogenesis is initiated.

    when disrupted = spontaneous adipogenesis
  • In Wnt signaling absence, myoblasts are reprogrammed to the adipocyte lineage and undergo spontaneous differentiation.
ZMPSTE24GeneProduct10269 (Entrez Gene)

Annotated Interactions

No annotated interactions

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