Influence of laminopathies on Wnt signaling (Homo sapiens)

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26, 22911259362125Impaired expansion/ differentiationof WAT+ feedbackWnt target genesAdipocyte genesPreadipocytesHuman MSCPreadipogenic genesAdipocytesAdipogenic Stimuli16MyoblastOsteoblastCCND1AdiponectinSLC2A4MIRLET7B18Wnt SignalingWnt SignalingPPAR-γCEBPDCEBPB72CEBPAWNT10B1526S Proteasome DegredationGSK3B8, 10CSNK1A1CTNNB1CSNK1A1LAPCAXIN1CTNNB1CTNNB1LEF1TCF7TCF7L2TCF7L1CTNNB1aaXNull mutationsCaaX group15 amino acidsZMPSTE24Prelamin-ALMNAIsoprenylcysteine carboxyl methyltransferase CFarnesyltransferasePrelamin-ACaaX groupPrelamin-APrelamin-ACZMPSTE24CMature lamin ACo-localisationSREBP1c17MIR33BPrelamin-A9Prelamin-ASREBP1c12PPARG5, 20SREBP Signaling14, 23Restrictive DermopathyTruncated Prelamin-A13, 19RISC complexCDK6AGO2TARBP2HMGA2DICER1MIR33B4SPP1RUNX2TLE1Hutchinson-Gilford Progeria SyndromeHES1HES5ProgerinNotch SignalingHigh Bone TurnoverEMDEmerinCTNNB1EmerinFamilial Partial LIpodystrophyCH3Process with unknown interacting molecules PhosphateUbiquitinFarnesyl GroupLaminopathic signalingEmerin24TOR1AIP1Mature 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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Bibliography

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  1. 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 PubMed Europe PMC Scholia
  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 PubMed Europe PMC Scholia
  3. Christodoulides C, Lagathu C, Sethi JK, Vidal-Puig A; ''Adipogenesis and WNT signalling''; Trends Endocrinol Metab, 2009 PubMed Europe PMC Scholia
  4. 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 PubMed Europe PMC Scholia
  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 PubMed Europe PMC Scholia
  6. 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 PubMed Europe PMC Scholia
  7. 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 PubMed Europe PMC Scholia
  8. Markiewicz, E, Tilgner, K, Barker, N, van de Wetering, M, Clevers, H, Dorobek, M, Hausmanowa-Petrusewicz, I, Ramaekers, F. C. S, Broers, J. L. V, Blankesteijn, W. M, Salpingidou, G, Wilson, R. G, Ellis, J. A, Hutchison, C. J; ''The inner nuclear membrane protein Emerin regulates b-catenin activity by restricting its accumulation in the nucleus''; The EMBO Journal, 25, 3275-85, 2006 PubMed Europe PMC Scholia
  9. 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 PubMed Europe PMC Scholia
  10. 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 PubMed Europe PMC Scholia
  11. 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 Scholia
  12. 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 PubMed Europe PMC Scholia
  13. Pratt AJ, MacRae IJ; ''The RNA-induced silencing complex: a versatile gene-silencing machine.''; J Biol Chem, 2009 PubMed Europe PMC Scholia
  14. Akiyama, T; ''Wnt/beta-catenin signaling''; Cytokine Growth Factor Reviews, 11(4),273-282 , 2000 PubMed Europe PMC Scholia
  15. 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 PubMed Europe PMC Scholia
  16. Voronkov, A, Krauss, S; ''Wnt/beta-Catenin Signaling and Small Molecule Inhibitors''; Current Pharmaceutical Design,19, 634-664, 2013 PubMed Europe PMC Scholia
  17. Ramji, D. P, Foka, P; ''CCAAT/enhancer-binding proteins: structure, function and regulation''; Biochem. J, 365, 561–575, 2002 PubMed Europe PMC Scholia
  18. Ling, L, Nurcombe, V, Cool, S. M; ''Wnt signaling controls the fate of mesenchymal stem cells''; Gene, 433(1-2), 1-7, 2009 PubMed Europe PMC Scholia
  19. 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 PubMed Europe PMC Scholia

History

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CompareRevisionActionTimeUserComment
134352view05:39, 21 July 2024EgonwRemoved a template comment
128837view02:35, 23 February 2024EweitzModified description
128836view02:30, 23 February 2024EweitzLabel nucleus, refine alignment, standardize case
128835view02:23, 23 February 2024EweitzUpgrade legend
128834view02:15, 23 February 2024EweitzFix typo, economize layout
128833view00:55, 23 February 2024EweitzOntology Term : 'mesenchymal stem cell' added !
128832view00:54, 23 February 2024EweitzOntology Term : 'myoblast' added !
128831view00:54, 23 February 2024EweitzOntology Term : 'osteoblast' added !
128830view00:51, 23 February 2024EweitzEconomize layout
128829view00:36, 23 February 2024EweitzEconomize layout
128828view00:24, 23 February 2024EweitzEconomize layout
128827view00:07, 23 February 2024EweitzOntology Term : 'adipocyte' added !
128826view00:01, 23 February 2024EweitzFix typos, standardize case
128825view23:57, 22 February 2024EweitzOntology Term : 'Wnt signaling pathway' added !
123491view04:49, 29 July 2022EgonwMade a pathway clickable
120398view09:02, 30 November 2021Fehrhartsmall graphical change, boxed pathway nodes
119115view16:02, 17 June 2021FinterlyCleaned up biopax, removed duplicates, fixed biopaxrefs, added missing PMIDs
117842view15:13, 22 May 2021EweitzModified title
112235view17:51, 6 October 2020EgonwModified title
110306view06:47, 3 May 2020EgonwReplaced secondary ChEBI identifiers with a primary identifiers.
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.
Wnt Signaling
ZMPSTE24GeneProduct10269 (Entrez Gene)

Annotated Interactions

No annotated interactions

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