Atlas of Genetics and Cytogenetics

in Oncology and Haematology

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Gene Section Short Communication

MARCKS (myristoylated -rich kinase C substrate) Atsuhiro Tanabe, Maho Saito Division of Biochemistry, Department of Bioscience and Engineering, Shibaura Institute of Technology, Saitama, Japan (AT, MS)

Published in Atlas Database: November 2012 Online updated version : http://AtlasGeneticsOncology.org/Genes/MARCKSID50926ch6q21.html DOI: 10.4267/2042/48868 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2013 Atlas of Genetics and Cytogenetics in Oncology and Haematology

The mRNA has 996 bp open reading frame. The Identity promoter region has no TATA box and contained Other names: 80K-L, MACS, PKCSL, PRKCSL multiple transcription initiation sites in a region HGNC (Hugo): MARCKS spanning 57 base pairs (bp) (Harlan et al., 1991). Location: 6q21 Protein DNA/RNA Note MARCKS was cloned as a C (PKC) Note substrate. The MARCKS is located 6q21 The protein binds plasma membrane via N-terminus (114178527..114184652). and the phosphorylation site domain Transcription (PSD), which is also called effector domain (ED), with The transcription product is 6,1 kb with 2 exons. electrostatic interaction. MARCKS interacts with , , PIP 2 on the PSD.

Figure 1. A) MARCKS location on 6 is indicated. MARCKS gene starts at 114178527 and ends at 114184652. B) MARCKS gene is indicated. It has two exons and one intron.

Atlas Genet Cytogenet Oncol Haematol. 2013; 17(4) 266 MARCKS (myristoylated alanine-rich substrate) Tanabe A, Saito M

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 and/or movement of some type of cells (Brooks et al.,1996; Zhao et al., 2000; Weimer et al., 2009). Phosphorylation of MARCKS is instrumental in its MARCKS plays a vital role in the normal redistribution. MARCKS possesses a basic developmental processes of neurulation, hemisphere phosphorylation site domain (PSD). Phosphorylation of fusion, forebrain commissure formation, and formation this PSD domain prevents the electrostatic interaction of cortical and retinal laminations (Stumpo et al., of the effector region of the MARCKS to the plasma 1995). Long-term potentiation (LTP) is significantly membrane (George and Blackshear, 1992; Taniguchi impaired in the mossy fiber-CA3 pathway in MARCKS and Manenti, 1993; Kim et al., 1994). heterozygous mutant mice (Hussain et al., 2006). Expression Homology The MARCKS protein is highly expressed in the brain, Human MARCKS protein (332 amino ) was spleen, and lung, and is virtually absent in skeletal approximately 89, 74, and 59% identical to the bovine, muscle and liver in adult animal (Stumpo et al., 1989; mouse, and chicken . N-terminal domain and Blackshear et al., 1986; Albert et al., 1986). phosphorylation site domain (PSD) are highly- Localisation conserved between species (from human to Xenopus). Dephosphorylated and phosphorylated MARCKS are located at plasma membrane and in cytosol, Implicated in respectively. Melanoma Function Note MARCKS closs-links actin filament (Yarmola et al., In MARCKS over expressed human tumor-derived 2001) and changes cell morphology responsing to cell choroidal melanoma cells (OCM-1) the growth was stimulations in its phosphorylation/dephosphorylation- reduced by 35-40% when compared with control cells dependent manner (Tanabe et al., 2012). MARCKS (Manenti et al., 1998). In a highly motile melanoma participates in thrombin-induced noradrenaline release cell line WM-1617 melanoma cells nonphosphorylated from platelets (Elzagallaai et al., 2001) and PMA- or MARCKS works as an adhesion stabilizer (Estrada- bonbesin-induced neurotensin release from BON cells Bernal et al., 2009). (Li et al., 2005). MARCKS regulates the proliferation

Atlas Genet Cytogenet Oncol Haematol. 2013; 17(4) 267 MARCKS (myristoylated alanine-rich protein kinase C substrate) Tanabe A, Saito M

Alzheimer disease (AD) choroidal melanoma cells affects cell proliferation. Cancer Res. 1998 Apr 1;58(7):1429-34 Note Kimura T, Yamamoto H, Takamatsu J, Yuzuriha T, Miyamoto PKC-induced phosphorylation of MARCKS in cortical E, Miyakawa T. Phosphorylation of MARCKS in Alzheimer neurons in AD brains was weaker than that in control disease brains. Neuroreport. 2000 Mar 20;11(4):869-73 brains. However, phosphorylation of MARCKS was Zhao Y, Neltner BS, Davis HW. Role of MARCKS in regulating detected in microglia and dystrophic neurites within endothelial cell proliferation. Am J Physiol Cell Physiol. 2000 neuritic plaques (Kimura et al., 2000). In microglia Nov;279(5):C1611-20 amyloid β induces phosphorylation of MARCKS Elzagallaai A, Rosé SD, Brandan NC, Trifaró JM. Myristoylated through mitogen-activatd protein kinase (MAPK) alanine-rich C kinase substrate phosphorylation is involved in (Hasegawa et al., 2001) and PKC δ (Nakai et al., 2001). thrombin-induced serotonin release from platelets. Br J Haematol. 2001 Mar;112(3):593-602 References Hasegawa H, Nakai M, Tanimukai S, Taniguchi T, Terashima A, Kawamata T, Fukunaga K, Miyamoto E, Misaki K, Mukai H, Albert KA, Walaas SI, Wang JK, Greengard P. Widespread Tanaka C. Microglial signaling by amyloid beta protein through occurrence of "87 kDa," a major specific substrate for protein mitogen-activated protein kinase mediating phosphorylation of kinase C. Proc Natl Acad Sci U S A. 1986 May;83(9):2822-6 MARCKS. Neuroreport. 2001 Aug 8;12(11):2567-71 Blackshear PJ, Wen L, Glynn BP, Witters LA. Protein kinase Nakai M, Tanimukai S, Yagi K, Saito N, Taniguchi T, C-stimulated phosphorylation in vitro of a Mr 80,000 protein Terashima A, Kawamata T, Yamamoto H, Fukunaga K, phosphorylated in response to phorbol esters and growth Miyamoto E, Tanaka C. Amyloid beta protein activates PKC- factors in intact fibroblasts. Distinction from protein kinase C delta and induces translocation of myristoylated alanine-rich C and prominence in brain. J Biol Chem. 1986 Jan kinase substrate (MARCKS) in microglia. Neurochem Int. 2001 25;261(3):1459-69 Jun;38(7):593-600 Stumpo DJ, Graff JM, Albert KA, Greengard P, Blackshear PJ. Yarmola EG, Edison AS, Lenox RH, Bubb MR. Actin filament Molecular cloning, characterization, and expression of a cDNA cross-linking by MARCKS: characterization of two actin-binding encoding the "80- to 87-kDa" myristoylated alanine-rich C sites within the phosphorylation site domain. J Biol Chem. kinase substrate: a major cellular substrate for protein kinase 2001 Jun 22;276(25):22351-8 C. Proc Natl Acad Sci U S A. 1989 Jun;86(11):4012-6 Li J, O'Connor KL, Greeley GH Jr, Blackshear PJ, Townsend Harlan DM, Graff JM, Stumpo DJ, Eddy RL Jr, Shows TB, CM Jr, Evers BM. Myristoylated alanine-rich C kinase Boyle JM, Blackshear PJ. The human myristoylated alanine- substrate-mediated neurotensin release via protein kinase C- rich C kinase substrate (MARCKS) gene (MACS). Analysis of delta downstream of the Rho/ROK pathway. J Biol Chem. 2005 its gene product, promoter, and chromosomal localization. J Mar 4;280(9):8351-7 Biol Chem. 1991 Aug 5;266(22):14399-405 Hussain RJ, Stumpo DJ, Blackshear PJ, Lenox RH, Abel T, George DJ, Blackshear PJ. Membrane association of the McNamara RK. Myristoylated alanine rich C kinase substrate myristoylated alanine-rich C kinase substrate (MARCKS) (MARCKS) heterozygous mutant mice exhibit deficits in protein appears to involve myristate-dependent binding in the hippocampal mossy fiber-CA3 long-term potentiation. absence of a myristoyl protein receptor. J Biol Chem. 1992 Hippocampus. 2006;16(5):495-503 Dec 5;267(34):24879-85 Estrada-Bernal A, Gatlin JC, Sunpaweravong S, Pfenninger Taniguchi H, Manenti S. Interaction of myristoylated alanine- KH. Dynamic adhesions and MARCKS in melanoma cells. J rich protein kinase C substrate (MARCKS) with membrane Cell Sci. 2009 Jul 1;122(Pt 13):2300-10 phospholipids. J Biol Chem. 1993 May 15;268(14):9960-3 Weimer JM, Yokota Y, Stanco A, Stumpo DJ, Blackshear PJ, Kim J, Shishido T, Jiang X, Aderem A, McLaughlin S. Anton ES. MARCKS modulates radial progenitor placement, Phosphorylation, high ionic strength, and calmodulin reverse proliferation and organization in the developing cerebral cortex. the binding of MARCKS to phospholipid vesicles. J Biol Chem. Development. 2009 Sep;136(17):2965-75 1994 Nov 11;269(45):28214-9 Tanabe A, Shiraishi M, Negishi M, Saito N, Tanabe M, Sasaki Stumpo DJ, Bock CB, Tuttle JS, Blackshear PJ. MARCKS Y. MARCKS dephosphorylation is involved in bradykinin- deficiency in mice leads to abnormal brain development and induced neurite outgrowth in neuroblastoma SH-SY5Y cells. J perinatal death. Proc Natl Acad Sci U S A. 1995 Feb Cell Physiol. 2012 Feb;227(2):618-29 14;92(4):944-8 This article should be referenced as such: Brooks G, Brooks SF, Goss MW. MARCKS functions as a novel growth suppressor in cells of melanocyte origin. Tanabe A, Saito M. MARCKS (myristoylated alanine-rich Carcinogenesis. 1996 Apr;17(4):683-9 protein kinase C substrate). Atlas Genet Cytogenet Oncol Haematol. 2013; 17(4):266-268. Manenti S, Malecaze F, Chap H, Darbon JM. Overexpression of the myristoylated alanine-rich C kinase substrate in human

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