Influence of laminopathies on Wnt signaling (WP4844)

Homo sapiens

This pathway represents the different molecular interactions that may occur following the dis-regulation of signaling pathways in adipocyte differentiation and proliferation. That may result in the abnormal distribution of white adipose tissue, leading to the onset of lipodystrophic syndromes. This laminopathic pathway stems from mutations mainly occurring in the LMNA gene, and 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 in such phenotypic diseases.

Authors

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

Activity

last edited

Discuss this pathway

Check for ongoing discussions or start your own.

Cited In

Are you planning to include this pathway in your next publication? See How to Cite and add a link here to your paper once it's online.

Organisms

Homo sapiens

Communities

Rare Diseases

Annotations

Cell Type Ontology

osteoblast mesenchymal stem cell fat cell myoblast

Pathway Ontology

Wnt signaling pathway disease pathway

Disease Ontology

progeria

Participants

Label Type Compact URI Comment
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
PPARG 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
LEF1 GeneProduct ncbigene:51176
TCF7 GeneProduct ncbigene:6932
TCF7L2 GeneProduct ncbigene:6934
TCF7L1 GeneProduct ncbigene:83439
ZMPSTE24 GeneProduct ncbigene:10269
LMNA GeneProduct ncbigene:4000 Single point mutations = AD-EMD
Isoprenylcysteine carboxyl methyltransferase GeneProduct ncbigene:23463
Farnesyltransferase GeneProduct ncbigene:2339
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.
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
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
TOR1AIP1 GeneProduct ncbigene:26092
Adiponectin Protein uniprot:Q15848 glucose regulation and fatty acid oxidation metabolism --> is secreated from adipose tissue
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

References

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