MARCKS (myristoylated alanine-rich protein kinase C substrate)

2012-11-01 Atsuhiro Tanabe , Maho Saito Affiliation

Division of Biochemistry, Department of Bioscience, Engineering, Shibaura Institute of Technology, Saitama, Japan

Identity

HGNC

MARCKS

LOCATION

6q21

IMAGE

LEGEND

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.

LOCUSID

4082

ALIAS

80K-L,MACS,PKCSL,PRKCSL

FUSION GENES

Show Gene Fusions

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).

Proteins

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

Entity name

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 name

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

Pubmed ID	Last Year	Title	Authors
3458242	1986	Widespread occurrence of "87 kDa," a major specific substrate for protein kinase C.	Albert KA et al
3080427	1986	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 et al
8625478	1996	MARCKS functions as a novel growth suppressor in cells of melanocyte origin.	Brooks G et al
11260059	2001	Myristoylated alanine-rich C kinase substrate phosphorylation is involved in thrombin-induced serotonin release from platelets.	Elzagallaai A et al
19509053	2009	Dynamic adhesions and MARCKS in melanoma cells.	Estrada-Bernal A et al
1332970	1992	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 et al
1860846	1991	The human myristoylated alanine-rich C kinase substrate (MARCKS) gene (MACS). Analysis of its gene product, promoter, and chromosomal localization.	Harlan DM et al
11496150	2001	Microglial signaling by amyloid beta protein through mitogen-activated protein kinase mediating phosphorylation of MARCKS.	Hasegawa H et al
16572394	2006	Myristoylated alanine rich C kinase substrate (MARCKS) heterozygous mutant mice exhibit deficits in hippocampal mossy fiber-CA3 long-term potentiation.	Hussain RJ et al
7961759	1994	Phosphorylation, high ionic strength, and calmodulin reverse the binding of MARCKS to phospholipid vesicles.	Kim J et al
10757536	2000	Phosphorylation of MARCKS in Alzheimer disease brains.	Kimura T et al
15623535	2005	Myristoylated alanine-rich C kinase substrate-mediated neurotensin release via protein kinase C-delta downstream of the Rho/ROK pathway.	Li J et al
9537244	1998	Overexpression of the myristoylated alanine-rich C kinase substrate in human choroidal melanoma cells affects cell proliferation.	Manenti S et al
11290384	2001	Amyloid beta protein activates PKC-delta and induces translocation of myristoylated alanine-rich C kinase substrate (MARCKS) in microglia.	Nakai M et al
7862670	1995	MARCKS deficiency in mice leads to abnormal brain development and perinatal death.	Stumpo DJ et al
2726763	1989	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 et al
21448919	2012	MARCKS dephosphorylation is involved in bradykinin-induced neurite outgrowth in neuroblastoma SH-SY5Y cells.	Tanabe A et al
8486722	1993	Interaction of myristoylated alanine-rich protein kinase C substrate (MARCKS) with membrane phospholipids.	Taniguchi H et al
19666823	2009	MARCKS modulates radial progenitor placement, proliferation and organization in the developing cerebral cortex.	Weimer JM et al
11294839	2001	Actin filament cross-linking by MARCKS: characterization of two actin-binding sites within the phosphorylation site domain.	Yarmola EG et al
11029309	2000	Role of MARCKS in regulating endothelial cell proliferation.	Zhao Y et al

Other Information

Locus ID:

NCBI: 4082
MIM: 177061
HGNC: 6759
Ensembl: ENSG00000277443

Variants:

dbSNP: 4082
ClinVar: 4082
TCGA: ENSG00000277443
COSMIC: MARCKS

RNA/Proteins

Gene ID	Transcript ID	Uniprot
ENSG00000277443	ENST00000612661	P29966

Expression (GTEx)

100

150

200

Adipose - Subcutaneous

Adipose - Visceral

Adrenal Gland

Artery - Aorta

Artery - Tibial

Bladder

Brain - Amygdala

Brain - Anterior cingulate cortex

Brain - Caudate

Brain - Cerebellar Hemisphere

Brain - Cerebellum

Brain - Cortex

Brain - Frontal Cortex

Brain - Hippocampus

Brain - Hypothalamus

Brain - Nucleus accumbens

Brain - Putamen

Brain - Spinal cord

Brain - Substantia nigra

Breast - Mammary Tissue

Cells - Cultured fibroblasts

Cells - EBV - transformed lymphocytes

Cervix - Ectocervix

Cervix - Endocervix

Colon - Sigmoid

Colon - Transverse

Esophagus - Gastroesophageal Junction

Esophagus - Mucosa

Esophagus - Muscularis

Fallopian Tube

Heart - Atrial Appendage

Heart - Left Ventricle

Kidney - Cortex

Kidney - Medulla

Liver

Lung

Minor Salivary Gland

Muscle - Skeletal

Nerve - Tibial

Ovary

Pancreas

Pituitary

Prostate

Skin - Not Sun Exposed

Skin - Sun Exposed

Small Intestine - Terminal Ileum

Spleen

Stomach

Testis

Thyroid

Uterus

Vagina

Whole Blood

Pathways

Pathway	Source	External ID
Fc gamma R-mediated phagocytosis	KEGG	ko04666
Fc gamma R-mediated phagocytosis	KEGG	hsa04666
MicroRNAs in cancer	KEGG	hsa05206
MicroRNAs in cancer	KEGG	ko05206
Metabolism	REACTOME	R-HSA-1430728
Integration of energy metabolism	REACTOME	R-HSA-163685
Regulation of insulin secretion	REACTOME	R-HSA-422356
Acetylcholine regulates insulin secretion	REACTOME	R-HSA-399997

Protein levels (Protein atlas)

Not detected

Low

Medium

High

References

Pubmed ID	Year	Title	Citations
19302977	2009	MicroRNA-21 directly targets MARCKS and promotes apoptosis resistance and invasion in prostate cancer cells.	109
11825894	2002	Myristoylated alanine-rich C kinase substrate (MARCKS) sequesters spin-labeled phosphatidylinositol 4,5-bisphosphate in lipid bilayers.	34
19773446	2009	Epidermal growth factor receptor variant III-induced glioma invasion is mediated through myristoylated alanine-rich protein kinase C substrate overexpression.	34
19574534	2010	Myristoylated alanine-rich C-kinase substrate (MARCKS) protein regulation of human neutrophil migration.	27
18055557	2007	Protein kinase C delta regulates airway mucin secretion via phosphorylation of MARCKS protein.	24
20047593	2010	Myristoylated alanine-rich C kinase substrate phosphorylation promotes cholangiocarcinoma cell migration and metastasis via the protein kinase C-dependent pathway.	24
14506265	2003	Direct involvement of protein myristoylation in myristoylated alanine-rich C kinase substrate (MARCKS)-calmodulin interaction.	22
25179733	2015	Targeting phospho-MARCKS overcomes drug-resistance and induces antitumor activity in preclinical models of multiple myeloma.	22
27119641	2016	Regulation of PI3K by PKC and MARCKS: Single-Molecule Analysis of a Reconstituted Signaling Pathway.	22
18940893	2009	MARCKS silencing differentially affects human vascular smooth muscle and endothelial cell phenotypes to inhibit neointimal hyperplasia in saphenous vein.	20

Citation

Atsuhiro Tanabe ; Maho Saito

MARCKS (myristoylated alanine-rich protein kinase C substrate)

Atlas Genet Cytogenet Oncol Haematol. 2012-11-01

Online version: http://atlasgeneticsoncology.org/gene/50926/marcks