Overlap between signal transduction pathways contributing to LMNA laminopathies (Homo sapiens)

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CREBBPP/CAF2929Prelamin-AC376110, 1515815276, 28, 4439, 584334151253, 5138Wnt target genes?Osteogenic genesSkeletal dysplasia / increased fatty deposits in bone marrow+ feedbackProliferationRb proteasomal degradationAdipocyte progenitorClonal expansionAcetyl groupLegendIncreased stimulation of the + feedback mechanism in ZMPSTE -/- cellsMis-localization to the ERUbiquitin-mediatedproteasome degradation-Human MSCRISC complex?Impaired expansion/ differentiationof WATNotch target genesG1/ S phase transitionLamin A intranuclear fociTerminal differentiation165592055Osteoblast progenitorTGFB1SMAD2JUNBSMAD3MIRLET7BMAN1WNT7BMyostatinP21NOTCH1BMP232231517Wnt signaling26S proteasome degradationGSK3B7, 47CSNK1A1CTNNB1CSNK1A1LAPCAXIN1CTNNB1CTNNB1LEF1TCF7TCF7L2TCF7L1CTNNB1aaXNull mutationsCaaX group15 amino acidsZMPSTE24Prelamin-ALMNAIsoprenylcysteine carboxyl methyltransferase 37CFarnesyltransferaseCaaX group37Prelamin-AZMPSTE24CLamin A37Co-localisationSREBP1c13MIR33B34Prelamin-A14SREBP1cSREBP SignalingRestrictive dermopathy12, 57Truncated prelamin-A42HMGA2TLE1Hutchinson-Gilford progeria syndromeHES1HES5ProgerinNotch signaling26Dunnigan-type familial partial lipodystrophyCH3Process with unknown interacting molecules PhosphateUbiquitinFarnesyl groupLaminopathic signalingEmerinCTNNB1WNT10B59PPARGCEBPACEBPD53CEBPBAdipocyte genes30Adipogenic stimulie.g. glutocorticoidsPrelamin-AAGO2TARBP2DICER1MIR33B463450Myogenic differentiation45, 52Dilated cardiomyopathyG1 PhaseOverexpression of proteins involved in oxidative metabolism19Tissue fibrosis in straited muscle60Mandibuloacral dysplasia A36S phaseIncreased osteoclastogenesis /osteoblast differentiation / ex matrix remodelingCell stimulationImpaired myoblast differentiation /myofiber degenerationMyogenic differentiationtargets Decreased nuclear stability / abnormal morphology /impaired mechanotransduction/decreased cytoskeletal stiffness21, 24CardiomyocyteCytoskeleton35Sacromeres2Altered lamin A Akt mediated phosphorylation / degradation36Rho mediated actin polymerization48, 50Preadipocyte senescence19Muscle fibers2Myocyte progenitorHistonesmechanical forceCell cycle Biochemical block / Apoptosis8Akt/mTOR signalingDNAROSContractile impairmentMyofiber defectsCell deathPI3K-AKT-mTOR signaling4MYOD136Emery-Dreifuss muscular dystrophyOsteoprotegerinMAOB4Oxidative damageNAP1L115RB1Cathepsin K36TGFB245MAOAMAPK/ERK signaling41CDK410Arrhythmogenic rightventricular cardiomyopathy/dilated cardiomyopathyHDAC1MYOD1HistonesRB133MAPK/ERK signalingLINC complex4122Actin11Prelamin A24Canonical NF-KB pathwayApoptosisLamin A56TGFB signaling5RUNX255TGFB signaling30Emerin54MAN1LAP2ALamin AEmerinPPARG49NUCLEAR LAMINA Lamin ALamin ANOTCH NICDEmerin---SPP131Terminal differentiationMYOD1E2F1S phase proteins ApoptosisE2F1P/CAFHDAC1RB1HDAC1E2F1


Description

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.

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Bibliography

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History

View all...
CompareRevisionActionTimeUserComment
134355view05:44, 21 July 2024EgonwRemoved template comments
128410view04:42, 4 February 2024EweitzUpgrade legend
128409view04:39, 4 February 2024EweitzModified description
128408view04:38, 4 February 2024EweitzFix typos, standardize case
128407view04:33, 4 February 2024EweitzFix typos, standardize case
123415view11:15, 25 July 2022EgonwMade another three pathways clickable
120399view09:06, 30 November 2021Fehrhartsmall graphical change, boxed pathway nodes
117843view15:15, 22 May 2021EweitzModified title
110990view15:02, 25 June 2020Fehrhartcorrected a few conversions and added states
110605view18:43, 20 May 2020ZoebaroisModified description
110604view18:33, 20 May 2020ZoebaroisModified title
110554view10:20, 18 May 2020ZoebaroisAddition of ? to whether prelamin A disregulates MAO activity- no concrete evidence available
110291view09:33, 2 May 2020EgonwSecond round of manual cleanup
110290view09:26, 2 May 2020EgonwFirst round of manual clean up of the Biopax xml
110289view09:06, 2 May 2020EgonwMore PubMed identifiers
110288view08:51, 2 May 2020EgonwAdded more PubMed identifiers
110287view08:37, 2 May 2020EgonwMore unicode fixes and added missing PubMed identifiers.
110286view08:28, 2 May 2020EgonwFixed more unicode issues
110285view08:18, 2 May 2020EgonwFixed unicode issues in a few references
110284view08:03, 2 May 2020EgonwReplaced secondary ChEBI identifiers with a primary identifiers.
110259view15:23, 30 April 2020EgonwReplaced a secondary ChEBI identifiers with a primary identifier.
110238view15:15, 29 April 2020EgonwNot a mim-conversion
110039view12:01, 14 April 2020ZoebaroisRemoval of interaction between TCF complex to RUNX2

Conversion arrow from MIR33B synthesis to RISC complex Modification of Rb/MyoD pathway in myoblast with addition of new references

Acetyl group in key changed to yellow
109987view07:36, 9 April 2020ZoebaroisReverted to version '07:31, 9 April 2020' by Zoebarois
109986view07:33, 9 April 2020ZoebaroisObject colours changed to grey
109985view07:31, 9 April 2020ZoebaroisOrganelles and cell objects changed to bold
109963view11:36, 8 April 2020ZoebaroisCorrection of farnesyl groups in lamin A processing
109959view08:32, 8 April 2020ZoebaroisProgerin increased stimulation of SPP1 in hMSC Reference added to SPP1 action of CEBP/B inhibition and RUNX2 stimulation
109957view06:41, 8 April 2020Fehrhartfixed unconnected lines
109909view14:17, 6 April 2020ZoebaroisRemoval of HMGA2 complex as was irrelevant to lipodystrophy

addition of'clonal expansion' and 'terminal differentiation' phase during adipogenesis negative regulation of HMGA2/ CEBPA/ PPARG by RISC complex

Reference added to impaired expansion/differentia
109906view11:41, 6 April 2020ZoebaroisReferences added to LNMA processing

BMPS/TGBFB1 singaling molecues added Notch Signaling regulation of GSK3B/ emerin/ NOTCH1 Dilated cardiomyopathy label added

Cell labels changed to progenitor
109878view13:13, 3 April 2020ZoebaroisModified title
109877view13:12, 3 April 2020ZoebaroisConnected the muscular laminopathic transduction pathway to Canconial Wnt signaling

seperated out the pro-adipogenic process from the HMSC and placed it into a differentiating adipocyte

Incorporated a TGF-B/Smad pathway for the expression of RUNX2 and my
109847view10:25, 2 April 2020ZoebaroisOntology Term : 'familial partial lipodystrophy' added !
109846view09:57, 2 April 2020ZoebaroisOntology Term : 'disease pathway' added !
109845view09:56, 2 April 2020ZoebaroisOntology Term : 'cardiomyopathy' added !
109844view09:56, 2 April 2020ZoebaroisOntology Term : 'Emery-Dreifuss muscular dystrophy' added !
109843view09:55, 2 April 2020ZoebaroisOntology Term : 'progeria' added !
109842view09:53, 2 April 2020ZoebaroisNew pathway

External references

DataNodes

View all...
NameTypeDatabase referenceComment
AGO2GeneProduct27161 (Entrez Gene)
APCGeneProduct324 (Entrez Gene)
AXIN1GeneProduct8312 (Entrez Gene)
ActinGeneProduct60 (Entrez Gene)
ApoptosisPathwayWP254 (WikiPathways)
Arrhythmogenic right

ventricular cardiomyopathy/

dilated cardiomyopathy		PathwayWP2118 (WikiPathways)
BMP2GeneProduct650 (Entrez Gene)
CMetaboliteCHEBI:17376 (ChEBI)
CDK4GeneProductENSG00000135446 (Ensembl)
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
CEBPDGeneProduct1052 (Entrez Gene)
CREBBPGeneProduct1387 (Entrez Gene)
  • involved in the acetylation of MYOD1, enabling it to activate myogenic differentiation targets
  • acetylates histones
CSNK1A1GeneProduct1452 (Entrez Gene)
CSNK1A1LGeneProduct122011 (Entrez Gene)
CTNNB1GeneProduct1499 (Entrez Gene)
Canonical NF-KB pathwayPathwayWP4562 (WikiPathways)
Cathepsin KProteinP43235 (Uniprot-TrEMBL)
DICER1GeneProduct23405 (Entrez Gene)
E2F1GeneProduct1869 (Entrez Gene)
EmerinProteinF8WEQ1 (Uniprot-TrEMBL)
EmerinProteinQ5HY57 (Uniprot-TrEMBL)
  • Q133H mutation showed no significant binding to f-actin
  • loss of emerin leads to dysregulation of myoD pathway
Emery-Dreifuss muscular dystrophyPathwayWP4535 (WikiPathways)
FarnesyltransferaseGeneProduct2339 (Entrez Gene)
GSK3BGeneProduct2932 (Entrez Gene)
HDAC1GeneProduct3065 (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
Hutchinson-Gilford progeria syndromePathwayWP4320 (WikiPathways)
Isoprenylcysteine carboxyl methyltransferase GeneProduct23463 (Entrez Gene)
JUNBGeneProduct3726 (Entrez Gene)
LAP2AGeneProduct7112 (Entrez Gene)
LEF1GeneProduct51176 (Entrez Gene)
LMNAGeneProduct4000 (Entrez Gene) Single point mutations = AD-EMD
Lamin AGeneProduct4000 (Entrez Gene)
MAN1ProteinQ9Y2U8 (Uniprot-TrEMBL)
MAOAGeneProduct4128 (Entrez Gene)
MAOBGeneProduct4129 (Entrez Gene)
MAPK/ERK signalingPathwayWP1845 (WikiPathways)
MIR33BGeneProduct693120 (Entrez Gene)
MIRLET7BGeneProduct406884 (Entrez Gene) targets HMGA2, decreasing it --> high amounts in mature adipocytes
MYOD1GeneProduct4654 (Entrez Gene)
MyostatinGeneProduct2660 (Entrez Gene)
NAP1L1GeneProduct4673 (Entrez Gene) removes acetylated histones providing an open structure of the chromatin
NOTCH NICDGeneProduct4851 (Entrez Gene)
NOTCH1GeneProduct4851 (Entrez Gene)
Notch signalingPathwayWP268 (WikiPathways)
OsteoprotegerinGeneProduct4982 (Entrez Gene) anti-osteoclastogenic cytokine
Oxidative damagePathwayWP3941 (WikiPathways)
P/CAFGeneProduct8850 (Entrez Gene)
P21GeneProduct1026 (Entrez Gene)
PI3K-AKT-mTOR signalingPathwayWP3844 (WikiPathways)
PPARGGeneProduct5468 (Entrez Gene) Novel F388L mutation is associated with a form of partial lipodystrophy
Prelamin AGeneProduct4000 (Entrez Gene)
  • mutated lamin A- impairements with emerin bidning - involved in its mislocalisation
  • lmna mutation R527H/ farnesylated laminA = MADA - increased TGFB2
Prelamin-AProteinD6RB20 (Uniprot-TrEMBL)
ProgerinGeneProduct4000 (Entrez Gene)
RB1GeneProduct5925 (Entrez Gene)
RUNX2GeneProduct860 (Entrez Gene)
SMAD2GeneProduct4087 (Entrez Gene)
SMAD3GeneProduct4088 (Entrez Gene)
SPP1GeneProduct6696 (Entrez Gene)
SREBP SignalingPathwayWP1982 (WikiPathways)
SREBP1cGeneProduct6720 (Entrez Gene)
TARBP2GeneProduct6895 (Entrez Gene)
TCF7GeneProduct6932 (Entrez Gene)
TCF7L1GeneProduct83439 (Entrez Gene)
TCF7L2GeneProduct6934 (Entrez Gene)
TGFB signalingPathwayWP2742 (WikiPathways)
  • overexpression = tissue fibrosis
  • lmna null/ mutated = deregulation of TGFB/smad pathway
TGFB1GeneProduct7040 (Entrez Gene)
TGFB2GeneProduct7042 (Entrez Gene)
  • lmna H222P mutation - modified interaction with TGFB2 - activation of Akt/mTOR signaling
  • is elavated in EDMD
TLE1GeneProduct7088 (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
WNT7BGeneProduct7477 (Entrez Gene)
Wnt signalingPathwayWP428 (WikiPathways)
ZMPSTE24GeneProduct10269 (Entrez Gene)

Annotated Interactions

No annotated interactions

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