Influence of laminopathies on Wnt signaling (WP4844)

Homo sapiens

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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Authors

Zoe Barois , Lauren J. Dupuis , Friederike Ehrhart , Egon Willighagen , Eric Weitz , and Finterly Hu

Cited In

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Organism

Homo sapiens

Communities

Rare Diseases

Annotations

Pathway Ontology: disease pathway

Disease Ontology: progeria

Participants

Label Type Compact Identifier Comment
C Metabolite chebi:17376
C Metabolite chebi:17376
C Metabolite chebi:17376
SLC2A4 GeneProduct ncbigene:6517 GLUT4- associated with noninsulin diabetes mellitus
MIRLET7B GeneProduct ncbigene:406884 targets HMGA2, decreasing it --> high amounts in mature adipocytes
CCND1 GeneProduct ncbigene:595
PPAR-γ GeneProduct ncbigene:5468 is down regulated following overexpression of miR33B
CEBPD GeneProduct ncbigene:1052
CEBPB GeneProduct ncbigene:1051 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
CEBPA GeneProduct ncbigene:1050 is down regulated following overexpression of miR33B
WNT10B GeneProduct ncbigene:7480 upregulation will stimulate wnt signaling to down regulate adipogenesis
GSK3B GeneProduct ncbigene:2932
CSNK1A1 GeneProduct ncbigene:1452
CTNNB1 GeneProduct ncbigene:1499
CSNK1A1L GeneProduct ncbigene:122011
APC GeneProduct ncbigene:324
AXIN1 GeneProduct ncbigene:8312
CTNNB1 GeneProduct ncbigene:1499
CTNNB1 GeneProduct ncbigene:1499
LEF1 GeneProduct ncbigene:51176
TCF7 GeneProduct ncbigene:6932
TCF7L2 GeneProduct ncbigene:6934
TCF7L1 GeneProduct ncbigene:83439
CTNNB1 GeneProduct ncbigene:1499
ZMPSTE24 GeneProduct ncbigene:10269
LMNA GeneProduct ncbigene:4000 Single point mutations = AD-EMD
Isoprenylcysteine carboxyl methyltransferase GeneProduct ncbigene:23463
Farnesyltransferase GeneProduct ncbigene:2339
ZMPSTE24 GeneProduct ncbigene:10269
Mature lamin A GeneProduct ncbigene:4000
SREBP1c GeneProduct ncbigene:6720
MIR33B GeneProduct ncbigene:693120 intronic microRNA located within the genes encoding SREBP are transcribed in concert with their host genes and function alongside them to regulate cholesterol/FA and glucose metabolism
MIR33b is highly induced upon differentiation of human preadipocytes + SREBP1
inhibition of MiR-33b enhances lipid droplet accumilation + its overexpression impaired preadipocyte proliferation + PPARG activation --> may be mediated by targeting HMGA2/CDK6+ others
overexpression of miR-33b causes reduced preadipocyte proliferation and impaired differentiation e inhibition of miR-33b enhanced lipid accumulation in differentiating adipocytes
negative regulator of adipogenesis, despite being highly upregulated during the later stages of adipocyte differentiation.
SREBP1c GeneProduct ncbigene:6720
PPARG GeneProduct ncbigene:5468 Novel F388L mutation is associated with a form of partial lipodystrophy
CDK6 GeneProduct ncbigene:1021
AGO2 GeneProduct ncbigene:27161
TARBP2 GeneProduct ncbigene:6895
HMGA2 GeneProduct ncbigene:8091 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
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DICER1 GeneProduct ncbigene:23405
MIR33B GeneProduct ncbigene:693120
SPP1 GeneProduct ncbigene:6696
RUNX2 GeneProduct ncbigene:860
TLE1 GeneProduct ncbigene:7088
HES1 GeneProduct ncbigene:3280
HES5 GeneProduct ncbigene:388585
Progerin GeneProduct ncbigene:4000
EMD GeneProduct ncbigene:2010 Mutations are linked to X-EMD
CTNNB1 GeneProduct ncbigene:1499
TOR1AIP1 GeneProduct ncbigene:26092
Mature lamin A GeneProduct ncbigene:4000
Adiponectin Protein uniprot:Q15848 glucose regulation and fatty acid oxidation metabolism --> is secreated from adipose tissue
Prelamin-A Protein uniprot:D6RB20
Prelamin-A Protein uniprot:D6RB20
Prelamin-A Protein uniprot:D6RB20
Prelamin-A Protein uniprot:D6RB20
Prelamin-A Protein uniprot:D6RB20
Prelamin-A Protein uniprot:D6RB20
Truncated Prelamin-A Protein uniprot:D6RB20 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
Emerin Protein uniprot:F8WEQ1
Emerin Protein uniprot:F8WEQ1
Emerin Protein uniprot:F8WEQ1
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References

  1. Wang X, Sato R, Brown MS, Hua X, Goldstein JL. SREBP-1, a membrane-bound transcription factor released by sterol-regulated proteolysis. Cell. 1994 Apr 8;77(1):53–62. PubMed Europe PMC Scholia
  2. Sinensky M, Fantle K, Trujillo M, McLain T, Kupfer A, Dalton M. The processing pathway of prelamin A. J Cell Sci. 1994 Jan;107 ( Pt 1):61–7. PubMed Europe PMC Scholia
  3. Aberle H, Bauer A, Stappert J, Kispert A, Kemler R. beta-catenin is a target for the ubiquitin-proteasome pathway. EMBO J. 1997 Jul 1;16(13):3797–804. PubMed Europe PMC Scholia
  4. Clements L, Manilal S, Love DR, Morris GE. Direct interaction between emerin and lamin A. Biochem Biophys Res Commun. 2000 Jan 27;267(3):709–14. PubMed Europe PMC Scholia
  5. Ross SE, Hemati N, Longo KA, Bennett CN, Lucas PC, Erickson RL, et al. Inhibition of adipogenesis by Wnt signaling. Science. 2000 Aug 11;289(5481):950–3. PubMed Europe PMC Scholia
  6. Akiyama T. Wnt/beta-catenin signaling. Cytokine Growth Factor Rev. 2000 Dec;11(4):273–82. PubMed Europe PMC Scholia
  7. Lloyd DJ, Trembath RC, Shackleton S. A novel interaction between lamin A and SREBP1: implications for partial lipodystrophy and other laminopathies. Hum Mol Genet. 2002 Apr 1;11(7):769–77. PubMed Europe PMC Scholia
  8. Ramji DP, Foka P. CCAAT/enhancer-binding proteins: structure, function and regulation. Biochem J. 2002 Aug 1;365(Pt 3):561–75. PubMed Europe PMC Scholia
  9. Hegele RA, Cao H, Frankowski C, Mathews ST, Leff T. PPARG F388L, a transactivation-deficient mutant, in familial partial lipodystrophy. Diabetes. 2002 Dec;51(12):3586–90. PubMed Europe PMC Scholia
  10. De Boer J, Wang HJ, Van Blitterswijk C. Effects of Wnt signaling on proliferation and differentiation of human mesenchymal stem cells. Tissue Eng. 2004;10(3–4):393–401. PubMed Europe PMC Scholia
  11. Navarro CL, De Sandre-Giovannoli A, Bernard R, Boccaccio I, Boyer A, Geneviève D, et al. Lamin A and ZMPSTE24 (FACE-1) defects cause nuclear disorganization and identify restrictive dermopathy as a lethal neonatal laminopathy. Hum Mol Genet. 2004 Oct 15;13(20):2493–503. PubMed Europe PMC Scholia
  12. Markiewicz E, Tilgner K, Barker N, van de Wetering M, Clevers H, Dorobek M, et al. The inner nuclear membrane protein emerin regulates beta-catenin activity by restricting its accumulation in the nucleus. EMBO J. 2006 Jul 26;25(14):3275–85. PubMed Europe PMC Scholia
  13. Christodoulides C, Lagathu C, Sethi JK, Vidal-Puig A. Adipogenesis and WNT signalling. Trends Endocrinol Metab. 2009 Jan;20(1):16–24. PubMed Europe PMC Scholia
  14. Ling L, Nurcombe V, Cool SM. Wnt signaling controls the fate of mesenchymal stem cells. Gene. 2009 Mar 15;433(1–2):1–7. PubMed Europe PMC Scholia
  15. Sun T, Fu M, Bookout AL, Kliewer SA, Mangelsdorf DJ. MicroRNA let-7 regulates 3T3-L1 adipogenesis. Mol Endocrinol. 2009 Jun;23(6):925–31. PubMed Europe PMC Scholia
  16. Pratt AJ, MacRae IJ. The RNA-induced silencing complex: a versatile gene-silencing machine. J Biol Chem. 2009 Jul 3;284(27):17897–901. PubMed Europe PMC Scholia
  17. Voronkov A, Krauss S. Wnt/beta-catenin signaling and small molecule inhibitors. Curr Pharm Des. 2013;19(4):634–64. PubMed Europe PMC Scholia
  18. Guo L, Li X, Tang Q-Q. Transcriptional regulation of adipocyte differentiation: a central role for CCAAT/enhancer-binding protein (C/EBP) β. J Biol Chem. 2015 Jan 9;290(2):755–61. PubMed Europe PMC Scholia
  19. Price NL, Holtrup B, Kwei SL, Wabitsch M, Rodeheffer M, Bianchini L, et al. SREBP-1c/MicroRNA 33b Genomic Loci Control Adipocyte Differentiation. Mol Cell Biol. 2016 Feb 1;36(7):1180–93. PubMed Europe PMC Scholia