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MARCKS (myristoylated alanine-rich protein kinase C substrate)

Written2012-11Atsuhiro Tanabe, Maho Saito
Division of Biochemistry, Department of Bioscience, Engineering, Shibaura Institute of Technology, Saitama, Japan

(Note : for Links provided by Atlas : click)

Identity

Alias_namesMACS
myristoylated alanine-rich protein kinase C substrate (MARCKS
Alias_symbol (synonym)PKCSL
80K-L
HGNC (Hugo) MARCKS
LocusID (NCBI) 4082
Atlas_Id 50926
Location 6q21  [Link to chromosome band 6q21]
Location_base_pair Starts at 114178514 and ends at 114184652 bp from pter ( according to hg19-Feb_2009)  [Mapping MARCKS.png]
 
  Figure 1. A) MARCKS location on chromosome 6 is indicated. MARCKS gene starts at 114178527 and ends at 114184652. B) MARCKS gene is indicated. It has two exons and one intron.
Fusion genes
(updated 2016)
MARCKS (6q21) / MARCKS (6q21)

DNA/RNA

Note The MARCKS gene is located 6q21 (114178527..114184652).
Transcription The transcription product is 6,1 kb with 2 exons. The mRNA has 996 bp open reading frame. The promoter region has no TATA box and contained multiple transcription initiation sites in a region spanning 57 base pairs (bp) (Harlan et al., 1991).

Protein

Note MARCKS was cloned as a protein kinase C (PKC) substrate. The protein binds plasma membrane via N-terminus myristoylation and the phosphorylation site domain (PSD), which is also called effector domain (ED), with electrostatic interaction. MARCKS interacts with actin, calmodulin, PIP2 on the PSD.
 
  Figure 2. A) MARCKS phosphorylation site domain (PSD (also called effector domain (ED)) is shown. It is mainly consisted of basic amino asids (K and R) and has serin residues phosphorylatable by PKC (159, 163 and 170) and by ROCK (at least 159). B) Dephospho MARCKS binds to plasma membrane and cross-links actin. Phospho MARCKS detached from plasma membrane and disrupts actin filaments.
Description Phosphorylation of MARCKS is instrumental in its redistribution. MARCKS possesses a basic phosphorylation site domain (PSD). Phosphorylation of this PSD domain prevents the electrostatic interaction of the effector region of the MARCKS to the plasma membrane (George and Blackshear, 1992; Taniguchi and Manenti, 1993; Kim et al., 1994).
Expression The MARCKS protein is highly expressed in the brain, spleen, and lung, and is virtually absent in skeletal muscle and liver in adult animal (Stumpo et al., 1989; Blackshear et al., 1986; Albert et al., 1986).
Localisation Dephosphorylated and phosphorylated MARCKS are located at plasma membrane and in cytosol, respectively.
Function MARCKS closs-links actin filament (Yarmola et al., 2001) and changes cell morphology responsing to cell stimulations in its phosphorylation/dephosphorylation-dependent manner (Tanabe et al., 2012). MARCKS participates in thrombin-induced noradrenaline release from platelets (Elzagallaai et al., 2001) and PMA- or bonbesin-induced neurotensin release from BON cells (Li et al., 2005). MARCKS regulates the proliferation and/or movement of some type of cells (Brooks et al.,1996; Zhao et al., 2000; Weimer et al., 2009). MARCKS plays a vital role in the normal developmental processes of neurulation, hemisphere fusion, forebrain commissure formation, and formation of cortical and retinal laminations (Stumpo et al., 1995). Long-term potentiation (LTP) is significantly impaired in the mossy fiber-CA3 pathway in MARCKS heterozygous mutant mice (Hussain et al., 2006).
Homology Human MARCKS protein (332 amino acids) was approximately 89, 74, and 59% identical to the bovine, mouse, and chicken proteins. N-terminal domain and phosphorylation site domain (PSD) are highly-conserved between species (from human to Xenopus).

Implicated in

Note
Entity Melanoma
Note In MARCKS over expressed human tumor-derived choroidal melanoma cells (OCM-1) the growth was reduced by 35-40% when compared with control cells (Manenti et al., 1998). In a highly motile melanoma cell line WM-1617 melanoma cells nonphosphorylated MARCKS works as an adhesion stabilizer (Estrada-Bernal et al., 2009).
  
Entity Alzheimer disease (AD)
Note PKC-induced phosphorylation of MARCKS in cortical neurons in AD brains was weaker than that in control brains. However, phosphorylation of MARCKS was detected in microglia and dystrophic neurites within neuritic plaques (Kimura et al., 2000). In microglia amyloid β induces phosphorylation of MARCKS through mitogen-activatd protein kinase (MAPK) (Hasegawa et al., 2001) and PKCδ (Nakai et al., 2001).
  

Bibliography

Widespread occurrence of "87 kDa," a major specific substrate for protein kinase C.
Albert KA, Walaas SI, Wang JK, Greengard P.
Proc Natl Acad Sci U S A. 1986 May;83(9):2822-6.
PMID 3458242
 
Protein kinase C-stimulated phosphorylation in vitro of a Mr 80,000 protein phosphorylated in response to phorbol esters and growth factors in intact fibroblasts. Distinction from protein kinase C and prominence in brain.
Blackshear PJ, Wen L, Glynn BP, Witters LA.
J Biol Chem. 1986 Jan 25;261(3):1459-69.
PMID 3080427
 
MARCKS functions as a novel growth suppressor in cells of melanocyte origin.
Brooks G, Brooks SF, Goss MW.
Carcinogenesis. 1996 Apr;17(4):683-9.
PMID 8625478
 
Myristoylated alanine-rich C kinase substrate phosphorylation is involved in thrombin-induced serotonin release from platelets.
Elzagallaai A, Rose SD, Brandan NC, Trifaro JM.
Br J Haematol. 2001 Mar;112(3):593-602.
PMID 11260059
 
Dynamic adhesions and MARCKS in melanoma cells.
Estrada-Bernal A, Gatlin JC, Sunpaweravong S, Pfenninger KH.
J Cell Sci. 2009 Jul 1;122(Pt 13):2300-10. doi: 10.1242/jcs.047860. Epub 2009 Jun 9.
PMID 19509053
 
Membrane association of the myristoylated alanine-rich C kinase substrate (MARCKS) protein appears to involve myristate-dependent binding in the absence of a myristoyl protein receptor.
George DJ, Blackshear PJ.
J Biol Chem. 1992 Dec 5;267(34):24879-85.
PMID 1332970
 
The human myristoylated alanine-rich C kinase substrate (MARCKS) gene (MACS). Analysis of its gene product, promoter, and chromosomal localization.
Harlan DM, Graff JM, Stumpo DJ, Eddy RL Jr, Shows TB, Boyle JM, Blackshear PJ.
J Biol Chem. 1991 Aug 5;266(22):14399-405.
PMID 1860846
 
Microglial signaling by amyloid beta protein through mitogen-activated protein kinase mediating phosphorylation of MARCKS.
Hasegawa H, Nakai M, Tanimukai S, Taniguchi T, Terashima A, Kawamata T, Fukunaga K, Miyamoto E, Misaki K, Mukai H, Tanaka C.
Neuroreport. 2001 Aug 8;12(11):2567-71.
PMID 11496150
 
Myristoylated alanine rich C kinase substrate (MARCKS) heterozygous mutant mice exhibit deficits in hippocampal mossy fiber-CA3 long-term potentiation.
Hussain RJ, Stumpo DJ, Blackshear PJ, Lenox RH, Abel T, McNamara RK.
Hippocampus. 2006;16(5):495-503.
PMID 16572394
 
Phosphorylation, high ionic strength, and calmodulin reverse the binding of MARCKS to phospholipid vesicles.
Kim J, Shishido T, Jiang X, Aderem A, McLaughlin S.
J Biol Chem. 1994 Nov 11;269(45):28214-9.
PMID 7961759
 
Phosphorylation of MARCKS in Alzheimer disease brains.
Kimura T, Yamamoto H, Takamatsu J, Yuzuriha T, Miyamoto E, Miyakawa T.
Neuroreport. 2000 Mar 20;11(4):869-73.
PMID 10757536
 
Myristoylated alanine-rich C kinase substrate-mediated neurotensin release via protein kinase C-delta downstream of the Rho/ROK pathway.
Li J, O'Connor KL, Greeley GH Jr, Blackshear PJ, Townsend CM Jr, Evers BM.
J Biol Chem. 2005 Mar 4;280(9):8351-7. Epub 2004 Dec 28.
PMID 15623535
 
Overexpression of the myristoylated alanine-rich C kinase substrate in human choroidal melanoma cells affects cell proliferation.
Manenti S, Malecaze F, Chap H, Darbon JM.
Cancer Res. 1998 Apr 1;58(7):1429-34.
PMID 9537244
 
Amyloid beta protein activates PKC-delta and induces translocation of myristoylated alanine-rich C kinase substrate (MARCKS) in microglia.
Nakai M, Tanimukai S, Yagi K, Saito N, Taniguchi T, Terashima A, Kawamata T, Yamamoto H, Fukunaga K, Miyamoto E, Tanaka C.
Neurochem Int. 2001 Jun;38(7):593-600.
PMID 11290384
 
MARCKS deficiency in mice leads to abnormal brain development and perinatal death.
Stumpo DJ, Bock CB, Tuttle JS, Blackshear PJ.
Proc Natl Acad Sci U S A. 1995 Feb 14;92(4):944-8.
PMID 7862670
 
Molecular cloning, characterization, and expression of a cDNA encoding the "80- to 87-kDa" myristoylated alanine-rich C kinase substrate: a major cellular substrate for protein kinase C.
Stumpo DJ, Graff JM, Albert KA, Greengard P, Blackshear PJ.
Proc Natl Acad Sci U S A. 1989 Jun;86(11):4012-6.
PMID 2726763
 
MARCKS dephosphorylation is involved in bradykinin-induced neurite outgrowth in neuroblastoma SH-SY5Y cells.
Tanabe A, Shiraishi M, Negishi M, Saito N, Tanabe M, Sasaki Y.
J Cell Physiol. 2012 Feb;227(2):618-29. doi: 10.1002/jcp.22763.
PMID 21448919
 
Interaction of myristoylated alanine-rich protein kinase C substrate (MARCKS) with membrane phospholipids.
Taniguchi H, Manenti S.
J Biol Chem. 1993 May 15;268(14):9960-3.
PMID 8486722
 
MARCKS modulates radial progenitor placement, proliferation and organization in the developing cerebral cortex.
Weimer JM, Yokota Y, Stanco A, Stumpo DJ, Blackshear PJ, Anton ES.
Development. 2009 Sep;136(17):2965-75. doi: 10.1242/dev.036616.
PMID 19666823
 
Actin filament cross-linking by MARCKS: characterization of two actin-binding sites within the phosphorylation site domain.
Yarmola EG, Edison AS, Lenox RH, Bubb MR.
J Biol Chem. 2001 Jun 22;276(25):22351-8. Epub 2001 Apr 6.
PMID 11294839
 
Role of MARCKS in regulating endothelial cell proliferation.
Zhao Y, Neltner BS, Davis HW.
Am J Physiol Cell Physiol. 2000 Nov;279(5):C1611-20.
PMID 11029309
 

Citation

This paper should be referenced as such :
Tanabe, A ; Saito, M
MARCKS (myristoylated alanine-rich protein kinase C substrate)
Atlas Genet Cytogenet Oncol Haematol. 2013;17(4):266-268.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://AtlasGeneticsOncology.org/Genes/MARCKSID50926ch6q21.html


External links

Nomenclature
HGNC (Hugo)MARCKS   6759
Cards
AtlasMARCKSID50926ch6q21
Entrez_Gene (NCBI)MARCKS  4082  myristoylated alanine rich protein kinase C substrate
Aliases80K-L; MACS; PKCSL; PRKCSL
GeneCards (Weizmann)MARCKS
Ensembl hg19 (Hinxton)ENSG00000277443 [Gene_View]  chr6:114178514-114184652 [Contig_View]  MARCKS [Vega]
Ensembl hg38 (Hinxton)ENSG00000277443 [Gene_View]  chr6:114178514-114184652 [Contig_View]  MARCKS [Vega]
ICGC DataPortalENSG00000277443
TCGA cBioPortalMARCKS
AceView (NCBI)MARCKS
Genatlas (Paris)MARCKS
WikiGenes4082
SOURCE (Princeton)MARCKS
Genetics Home Reference (NIH)MARCKS
Genomic and cartography
GoldenPath hg19 (UCSC)MARCKS  -     chr6:114178514-114184652 +  6q21   [Description]    (hg19-Feb_2009)
GoldenPath hg38 (UCSC)MARCKS  -     6q21   [Description]    (hg38-Dec_2013)
EnsemblMARCKS - 6q21 [CytoView hg19]  MARCKS - 6q21 [CytoView hg38]
Mapping of homologs : NCBIMARCKS [Mapview hg19]  MARCKS [Mapview hg38]
OMIM177061   
Gene and transcription
Genbank (Entrez)AI142997 AK027274 AK074526 AW163148 BC013004
RefSeq transcript (Entrez)NM_002356
RefSeq genomic (Entrez)NC_000006 NC_018917 NT_025741 NW_004929328
Consensus coding sequences : CCDS (NCBI)MARCKS
Cluster EST : UnigeneHs.712658 [ NCBI ]
CGAP (NCI)Hs.712658
Alternative Splicing GalleryENSG00000277443
Gene ExpressionMARCKS [ NCBI-GEO ]   MARCKS [ EBI - ARRAY_EXPRESS ]   MARCKS [ SEEK ]   MARCKS [ MEM ]
Gene Expression Viewer (FireBrowse)MARCKS [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevisibleExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)4082
GTEX Portal (Tissue expression)MARCKS
Protein : pattern, domain, 3D structure
UniProt/SwissProtP29966   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtP29966  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProP29966
Splice isoforms : SwissVarP29966
PhosPhoSitePlusP29966
Domaine pattern : Prosite (Expaxy)MARCKS_1 (PS00826)    MARCKS_2 (PS00827)   
Domains : Interpro (EBI)MARCKS   
Domain families : Pfam (Sanger)MARCKS (PF02063)   
Domain families : Pfam (NCBI)pfam02063   
Conserved Domain (NCBI)MARCKS
DMDM Disease mutations4082
Blocks (Seattle)MARCKS
SuperfamilyP29966
Human Protein AtlasENSG00000277443
Peptide AtlasP29966
HPRD07519
IPIIPI00219301   
Protein Interaction databases
DIP (DOE-UCLA)P29966
IntAct (EBI)P29966
FunCoupENSG00000277443
BioGRIDMARCKS
STRING (EMBL)MARCKS
ZODIACMARCKS
Ontologies - Pathways
QuickGOP29966
Ontology : AmiGOouter dense fiber  phosphatidylserine binding  ventricular cardiac muscle tissue development  protein kinase C binding  calmodulin binding  lysosome  centrosome  cytosol  microtubule  plasma membrane  focal adhesion  cell cortex  intracellular protein transport  actin filament organization  brain development  actin cytoskeleton  growth cone  activation of phospholipase D activity  cell-substrate adhesion  bleb  chromatoid body  germinal vesicle  dendritic spine  axon terminus  dendritic branch  regulation of insulin secretion  actin filament binding  positive regulation of dendritic spine morphogenesis  extracellular exosome  positive regulation of protein kinase C activity  positive regulation of glucose import in response to insulin stimulus  
Ontology : EGO-EBIouter dense fiber  phosphatidylserine binding  ventricular cardiac muscle tissue development  protein kinase C binding  calmodulin binding  lysosome  centrosome  cytosol  microtubule  plasma membrane  focal adhesion  cell cortex  intracellular protein transport  actin filament organization  brain development  actin cytoskeleton  growth cone  activation of phospholipase D activity  cell-substrate adhesion  bleb  chromatoid body  germinal vesicle  dendritic spine  axon terminus  dendritic branch  regulation of insulin secretion  actin filament binding  positive regulation of dendritic spine morphogenesis  extracellular exosome  positive regulation of protein kinase C activity  positive regulation of glucose import in response to insulin stimulus  
Pathways : BIOCARTAEffects of calcineurin in Keratinocyte Differentiation [Genes]   
Pathways : KEGGFc gamma R-mediated phagocytosis    MicroRNAs in cancer   
REACTOMEP29966 [protein]
REACTOME PathwaysR-HSA-399997 Acetylcholine regulates insulin secretion [pathway]
NDEx NetworkMARCKS
Atlas of Cancer Signalling NetworkMARCKS
Wikipedia pathwaysMARCKS
Orthology - Evolution
OrthoDB4082
GeneTree (enSembl)ENSG00000277443
Phylogenetic Trees/Animal Genes : TreeFamMARCKS
HOVERGENP29966
HOGENOMP29966
Homologs : HomoloGeneMARCKS
Homology/Alignments : Family Browser (UCSC)MARCKS
Gene fusions - Rearrangements
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerMARCKS [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)MARCKS
dbVarMARCKS
ClinVarMARCKS
1000_GenomesMARCKS 
Exome Variant ServerMARCKS
ExAC (Exome Aggregation Consortium)MARCKS (select the gene name)
Genetic variants : HAPMAP4082
Genomic Variants (DGV)MARCKS [DGVbeta]
DECIPHER (Syndromes)6:114178514-114184652  ENSG00000277443
CONAN: Copy Number AnalysisMARCKS 
Mutations
ICGC Data PortalMARCKS 
TCGA Data PortalMARCKS 
Broad Tumor PortalMARCKS
OASIS PortalMARCKS [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICMARCKS  [overview]  [genome browser]  [tissue]  [distribution]  
Mutations and Diseases : HGMDMARCKS
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
BioMutasearch MARCKS
DgiDB (Drug Gene Interaction Database)MARCKS
DoCM (Curated mutations)MARCKS (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)MARCKS (select a term)
intoGenMARCKS
NCG5 (London)MARCKS
Cancer3DMARCKS(select the gene name)
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM177061   
Orphanet
MedgenMARCKS
Genetic Testing Registry MARCKS
NextProtP29966 [Medical]
TSGene4082
GENETestsMARCKS
Huge Navigator MARCKS [HugePedia]
snp3D : Map Gene to Disease4082
BioCentury BCIQMARCKS
ClinGenMARCKS
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD4082
Chemical/Pharm GKB GenePA30637
Clinical trialMARCKS
Miscellaneous
canSAR (ICR)MARCKS (select the gene name)
Probes
Litterature
PubMed85 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMineMARCKS
EVEXMARCKS
GoPubMedMARCKS
iHOPMARCKS
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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