Overlap between signal transduction pathways contributing to LMNA laminopathies (WP4879)

Homo sapiens

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Laminopathies resulting form a range of LMNA mutations result in a range of tissue specific phenotypes. These rare diseases may be attributed to a symptomatic overlap characterized by the convergence of lamin A downstream signaling pathways. Lamin A is expressed in differentiating cells and thus this pathway highlights the major molecular signaling pathways misregulated during hMSC differentiation due to varying LMNA mutations.

Authors

Zoe Barois , Friederike Ehrhart , Egon Willighagen , and Eric Weitz

Activity

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Organisms

Homo sapiens

Communities

Rare Diseases

Annotations

Disease Ontology

progeria familial partial lipodystrophy cardiomyopathy Emery-Dreifuss muscular dystrophy

Pathway Ontology

disease pathway

Participants
Query Drugst.One

Label Type Compact URI Comment
C Metabolite chebi:17376
C Metabolite chebi:17376
C Metabolite chebi:17376
CREBBP GeneProduct ncbigene:1387 involved in the acetylation of MYOD1, enabling it to activate myogenic differentiation targets
acetylates histones
P/CAF GeneProduct ncbigene:8850
SMAD3 GeneProduct ncbigene:4088
Myostatin GeneProduct ncbigene:2660
WNT7B GeneProduct ncbigene:7477
P21 GeneProduct ncbigene:1026
MIRLET7B GeneProduct ncbigene:406884 targets HMGA2, decreasing it --> high amounts in mature adipocytes
JUNB GeneProduct ncbigene:3726
SMAD2 GeneProduct ncbigene:4087
NOTCH1 GeneProduct ncbigene:4851
BMP2 GeneProduct ncbigene:650
TGFB1 GeneProduct ncbigene:7040
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
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
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
Type your comment here
TLE1 GeneProduct ncbigene:7088
HES1 GeneProduct ncbigene:3280
HES5 GeneProduct ncbigene:388585
Progerin GeneProduct ncbigene:4000
CTNNB1 GeneProduct ncbigene:1499
WNT10B GeneProduct ncbigene:7480 upregulation will stimulate wnt signaling to down regulate adipogenesis
PPARG GeneProduct ncbigene:5468 is down regulated following overexpression of miR33B
CEBPA GeneProduct ncbigene:1050 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
Type your comment here
AGO2 GeneProduct ncbigene:27161
TARBP2 GeneProduct ncbigene:6895
DICER1 GeneProduct ncbigene:23405
MIR33B GeneProduct ncbigene:693120
MYOD1 GeneProduct ncbigene:4654
Osteoprotegerin GeneProduct ncbigene:4982 anti-osteoclastogenic cytokine
MAOB GeneProduct ncbigene:4129
NAP1L1 GeneProduct ncbigene:4673 removes acetylated histones providing an open structure of the chromatin
RB1 GeneProduct ncbigene:5925
TGFB2 GeneProduct ncbigene:7042 lmna H222P mutation - modified interaction with TGFB2 - activation of Akt/mTOR signaling
is elavated in EDMD
MAOA GeneProduct ncbigene:4128
CDK4 GeneProduct ensembl:ENSG00000135446
HDAC1 GeneProduct ncbigene:3065
MYOD1 GeneProduct ncbigene:4654
RB1 GeneProduct ncbigene:5925
Actin GeneProduct ncbigene:60
Prelamin A GeneProduct ncbigene:4000 mutated lamin A- impairements with emerin bidning - involved in its mislocalisation
lmna mutation R527H/ farnesylated laminA = MADA - increased TGFB2
Lamin A GeneProduct ncbigene:4000
RUNX2 GeneProduct ncbigene:860
LAP2A GeneProduct ncbigene:7112
Lamin A GeneProduct ncbigene:4000 mutated lamin A- impairements with emerin bidning - involved in its mislocalisation
lmna mutation R527H/ farnesylated laminA = MADA - increased TGFB2
PPARG GeneProduct ncbigene:5468 Novel F388L mutation is associated with a form of partial lipodystrophy
Lamin A GeneProduct ncbigene:4000
Lamin A GeneProduct ncbigene:4000
NOTCH NICD GeneProduct ncbigene:4851
SPP1 GeneProduct ncbigene:6696
MYOD1 GeneProduct ncbigene:4654
E2F1 GeneProduct ncbigene:1869
E2F1 GeneProduct ncbigene:1869
P/CAF GeneProduct ncbigene:8850
HDAC1 GeneProduct ncbigene:3065
RB1 GeneProduct ncbigene:5925
HDAC1 GeneProduct ncbigene:3065
E2F1 GeneProduct ncbigene:1869
Prelamin-A Protein uniprot:D6RB20
MAN1 Protein uniprot:Q9Y2U8
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
Prelamin-A Protein uniprot:D6RB20
Cathepsin K Protein uniprot:P43235
Emerin Protein uniprot:Q5HY57 mis-localisation to the ER with lamin A mutations = no propper nuclear localisation
Type your comment here
MAN1 Protein uniprot:Q9Y2U8
Emerin Protein uniprot:Q5HY57 Q133H mutation showed no significant binding to f-actin
loss of emerin leads to dysregulation of myoD pathway
Emerin Protein uniprot:Q5HY57 Q133H mutation showed no significant binding to f-actin
loss of emerin leads to dysregulation of myoD pathway

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