MARCKS explained

Myristoylated alanine-rich C-kinase substrate is a protein that in humans is encoded by the MARCKS gene.^{[1] [2] [3]} It plays important roles in cell shape, cell motility, secretion, transmembrane transport, regulation of the cell cycle, and neural development.^[4] Recently, MARCKS has been implicated in the exocytosis of a number of vesicles and granules such as mucin and chromaffin.It is also the name of a protein family, of which MARCKS is the most studied member. They are intrinsically disordered proteins, with an acidic pH, with high proportions of alanine, glycine, proline, and glutamic acid. They are membrane-bound through a lipid anchor at the N-terminus, and a polybasic domain in the middle. They are regulated by Ca²⁺/calmodulin and protein kinase C. In their unphosphorylated form, they bind to actin filaments, causing them to crosslink, and sequester acidic membrane phospholipids such as PIP2.

The protein encoded by this gene is a substrate for protein kinase C. It is localized to the plasma membrane and is an actin filament crosslinking protein. Phosphorylation by protein kinase C or binding to calcium-calmodulin inhibits its association with actin and with the plasma membrane, leading to its presence in the cytoplasm. The protein is thought to be involved in cell motility, phagocytosis, membrane trafficking and mitogenesis. MARCKS has been shown to regulate the Toll-like receptor pathway in macrophages^[5]

Interactions

MARCKS has been shown to interact with TOB1^[6] and with NMT2.^[7]

Further reading

• Aderem A . The MARCKS family of protein kinase-C substrates . Biochemical Society Transactions . 23 . 3 . 587–91 . August 1995 . 8566422 . 10.1042/bst0230587.
• Herget T, Brooks SF, Broad S, Rozengurt E . Relationship between the major protein kinase C substrates acidic 80-kDa protein-kinase-C substrate (80K) and myristoylated alanine-rich C-kinase substrate (MARCKS). Members of a gene family or equivalent genes in different species . European Journal of Biochemistry . 209 . 1 . 7–14 . October 1992 . 1396720 . 10.1111/j.1432-1033.1992.tb17255.x . free .
• Sakai K, Hirai M, Kudoh J, Minoshima S, Shimizu N . Molecular cloning and chromosomal mapping of a cDNA encoding human 80K-L protein: major substrate for protein kinase C . Genomics . 14 . 1 . 175–8 . September 1992 . 1427823 . 10.1016/S0888-7543(05)80301-5 .
• Harlan DM, Graff JM, Stumpo DJ, Eddy RL, Shows TB, Boyle JM, Blackshear PJ . The human myristoylated alanine-rich C kinase substrate (MARCKS) gene (MACS). Analysis of its gene product, promoter, and chromosomal localization . The Journal of Biological Chemistry . 266 . 22 . 14399–405 . August 1991 . 10.1016/S0021-9258(18)98698-9 . 1860846 . free .
• Graff JM, Stumpo DJ, Blackshear PJ . Characterization of the phosphorylation sites in the chicken and bovine myristoylated alanine-rich C kinase substrate protein, a prominent cellular substrate for protein kinase C . The Journal of Biological Chemistry . 264 . 20 . 11912–9 . July 1989 . 10.1016/S0021-9258(18)80153-3 . 2473066 . free .
• Herget T, Oehrlein SA, Pappin DJ, Rozengurt E, Parker PJ . The myristoylated alanine-rich C-kinase substrate (MARCKS) is sequentially phosphorylated by conventional, novel and atypical isotypes of protein kinase C . European Journal of Biochemistry . 233 . 2 . 448–57 . October 1995 . 7588787 . 10.1111/j.1432-1033.1995.448_2.x . free .
• Taniguchi H, Manenti S, Suzuki M, Titani K . Myristoylated alanine-rich C kinase substrate (MARCKS), a major protein kinase C substrate, is an in vivo substrate of proline-directed protein kinase(s). A mass spectroscopic analysis of the post-translational modifications . The Journal of Biological Chemistry . 269 . 28 . 18299–302 . July 1994 . 10.1016/S0021-9258(17)32304-9 . 8034575 . free .
• Rao PH, Murty VV, Gaidano G, Hauptschein R, Dalla-Favera R, Chaganti RS . Subregional mapping of 8 single copy loci to chromosome 6 by fluorescence in situ hybridization . Cytogenetics and Cell Genetics . 66 . 4 . 272–3 . 1994 . 8162705 . 10.1159/000133710 .
• Taniguchi H, Manenti S . Interaction of myristoylated alanine-rich protein kinase C substrate (MARCKS) with membrane phospholipids . The Journal of Biological Chemistry . 268 . 14 . 9960–3 . May 1993 . 10.1016/S0021-9258(18)82158-5 . 8486722 . free .
• Palmer RH, Schönwasser DC, Rahman D, Pappin DJ, Herget T, Parker PJ . PRK1 phosphorylates MARCKS at the PKC sites: serine 152, serine 156 and serine 163 . FEBS Letters . 378 . 3 . 281–5 . January 1996 . 8557118 . 10.1016/0014-5793(95)01454-3 . 46417714 . free .
• Swierczynski SL, Blackshear PJ . Myristoylation-dependent and electrostatic interactions exert independent effects on the membrane association of the myristoylated alanine-rich protein kinase C substrate protein in intact cells . The Journal of Biological Chemistry . 271 . 38 . 23424–30 . September 1996 . 8798548 . 10.1074/jbc.271.38.23424 . free .
• Spizz G, Blackshear PJ . Identification and characterization of cathepsin B as the cellular MARCKS cleaving enzyme . The Journal of Biological Chemistry . 272 . 38 . 23833–42 . September 1997 . 9295331 . 10.1074/jbc.272.38.23833 . free .
• Qi Q, Rajala RV, Anderson W, Jiang C, Rozwadowski K, Selvaraj G, Sharma R, Datla R . 6 . Molecular cloning, genomic organization, and biochemical characterization of myristoyl-CoA:protein N-myristoyltransferase from Arabidopsis thaliana . The Journal of Biological Chemistry . 275 . 13 . 9673–83 . March 2000 . 10734119 . 10.1074/jbc.275.13.9673 . free .
• Jin Cho S, La M, Ahn JK, Meadows GG, Joe CO . Tob-mediated cross-talk between MARCKS phosphorylation and ErbB-2 activation . Biochemical and Biophysical Research Communications . 283 . 2 . 273–7 . May 2001 . 11327693 . 10.1006/bbrc.2001.4773 .
• Li Y, Martin LD, Spizz G, Adler KB . MARCKS protein is a key molecule regulating mucin secretion by human airway epithelial cells in vitro . The Journal of Biological Chemistry . 276 . 44 . 40982–90 . November 2001 . 11533058 . 10.1074/jbc.M105614200 . free .
• Rauch ME, Ferguson CG, Prestwich GD, Cafiso DS . Myristoylated alanine-rich C kinase substrate (MARCKS) sequesters spin-labeled phosphatidylinositol 4,5-bisphosphate in lipid bilayers . The Journal of Biological Chemistry . 277 . 16 . 14068–76 . April 2002 . 11825894 . 10.1074/jbc.M109572200 . free .
• Alonso S, Dietrich U, Händel C, Käs JA, Bär M . Oscillations in the lateral pressure of lipid monolayers induced by nonlinear chemical dynamics of the second messengers MARCKS and protein kinase C . Biophysical Journal . 100 . 4 . 939–47 . February 2011 . 21320438 . 3037601 . 10.1016/j.bpj.2010.12.3702 . 2011BpJ...100..939A .
• Lippoldt J, Händel C, Dietrich U, Käs JA . Dynamic membrane structure induces temporal pattern formation . Biochimica et Biophysica Acta (BBA) - Biomembranes . 1838 . 10 . 2380–90 . October 2014 . 24866013 . 10.1016/j.bbamem.2014.05.018 . free .

Notes and References

1. Hartwig JH, Thelen M, Rosen A, Janmey PA, Nairn AC, Aderem A . MARCKS is an actin filament crosslinking protein regulated by protein kinase C and calcium-calmodulin . Nature . 356 . 6370 . 618–22 . April 1992 . 1560845 . 10.1038/356618a0 . 1992Natur.356..618H . 4252140 .
2. Blackshear PJ . The MARCKS family of cellular protein kinase C substrates . The Journal of Biological Chemistry . 268 . 3 . 1501–4 . January 1993 . 10.1016/S0021-9258(18)53878-3 . 8420923 . free .
3. Web site: Entrez Gene: MARCKS myristoylated alanine-rich protein kinase C substrate.
4. Prieto D, Zolessi FR . Functional Diversification of the Four MARCKS Family Members in Zebrafish Neural Development . Journal of Experimental Zoology Part B: Molecular and Developmental Evolution. 328 . 1–2 . 119–138 . January 2017 . 27554589 . 10.1002/jez.b.22691 . 2017JEZB..328..119P . 13263249 .
5. Issara-Amphorn J, Sjoelund VH, Smelkinson M, Montalvo S, Yoon SH, Manes NP, Nita-Lazar A . Myristoylated, alanine-rich C-kinase substrate (MARCKS) regulates toll-like receptor 4 signaling in macrophages . Scientific Reports . 13 . 1 . 19562 . 2023 . 37949888 . 10.1038/s41598-023-46266-x . 10543024 .
6. Jin Cho S, La M, Ahn JK, Meadows GG, Joe CO . Tob-mediated cross-talk between MARCKS phosphorylation and ErbB-2 activation . Biochemical and Biophysical Research Communications . 283 . 2 . 273–7 . May 2001 . 11327693 . 10.1006/bbrc.2001.4773 .
7. Selvakumar P, Lakshmikuttyamma A, Sharma RK . Biochemical characterization of bovine brain myristoyl-CoA:protein N-myristoyltransferase type 2 . Journal of Biomedicine & Biotechnology . 2009 . 907614 . 2009 . 19746168 . 2737134 . 10.1155/2009/907614 . free .