| 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. |
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| | 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. |
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| 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). |
| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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