MARCKS proteine

Fig. 7.10. Functions and regulation of protein kinase C. Receptor-controlled signal pathways lead to formation of the intracellular messenger substances and diacylglycerol (DAG), that, like phorbol ester (TPA), activate protein kinase C (PKC). Translocation to the cell membrane is linked with activation of protein kinase C receptors for protein kinase C, the RACK proteins, are also involved. Substrates of protein kinase C are the MARCKS proteins and other proteins associated with the cytoskeleton. Other substrates are the Raf kinase (see Chapter 10) and the receptor for vitamin D3 (VDR, see Chapter 4).

Of the many substrates of protein kinase C, the MARCKS proteins are highhghted as very well characterized and specific substrates of protein kinase C (review Aderem, 1995). The abbreviation MARCKS stands for myristoylated, alanine-rich C-kinase substrate. 

The MARCKS proteins are a family of proteins that are involved in physiologically important processes such as cell mobility, secretion, membrane transport and in regulation of the cell cycle. All these processes are associated with changes and restructuring of the actin cytoskeleton. The role of converting extracellular signals into changes in the structure of the actin cytoskeleton is attributed to the MARCKS proteins. A... 

Fig. 7.12. Functional domains or the MARCKS proteins. Linear representation of the characteristic domains of the MARCKS proteins. The Ser phosphorylation sites in the effector domain are underlined. The function of the MH2 domain is nnknown.

The MARCKS proteins are acidic proteins with a high content of the amino acids Ala, Gly, Pro and Glu. An N-terminal domain carries a lipid anchor in the form of myristinic acid, from which it is assumed that it mediates the association with the membrane. A basic effector domain is important for regulation of the MARCKS proteins a binding site for Ca calmoduhn and the phosphorylation site for protein kinase C are located in this domain (see Fig. 7.12). 

In the imphosphorylated form and in the absence of Ca, the MARCKS proteins bind to actin filaments and bring about crosshnking of the latter. Binding of Ca Vcal-modulin or phosphorylation by protein kinase C inhibits the crosslinking activity. The MARCKS proteins can thus modulate the aggregation status of actin filaments and function as effectors for the conversion of extracellular signals that are carried into the cell via G-protein-coupled receptors and/or tyrosine kinase receptors. 

Park J.A., Crews A.L., Lampe W.R., Fang S., Park J. and Adler K.B. (2007) Protein kinase C<5 regulates airway mucin secretion via phosphorylation of MARCKS protein. Am J Pathol. 171, 1822-1830... 

Protein phosphorylation is necessary for the initiation of cell proliferation. Myristoylated alanine-rich C kinase substrate (MARCKS) protein is one of the major PKC substrates. MARCKS phosphorylation may contribute to the morphological changes requiring the rearrangement... 

The effects of balanol and 10 -deoxybalanol on intact cells have been exmined to determine whether these compounds cross the cell membrane or if the potency and specificity observed in vitro are present in vivo. Western analysis showed that both compounds reduced phosphorylation of CREB in isoproterenol-stimulated A431 cells (ICso = 3 jM), although only balanol inhibits phosphorylation of MARCKS protein in phorbol ester-stimulated A431 cells (IC50 = 7 pM) 109],... 

Another type of myristoyl switch has been reported for the MRACKS proteins which are substrates of protein kinase C (see Section 7.4). The membrane binding of the MARCKS proteins is mediated by myristate plus basic motif. Protein kinase C phosphorylation within the basic motif introduces negative charges into the positively charged region. This reduces the electrostatic interactions with the acidic phospholipids and results in displacement of the MARCKS proteins from the membrane and into the cytosol. 

The members of the protein kinase C family are central signal proteins and, as such, are involved in the regulation of a multitude of cellular processes. A large number of substrates have been identified for which each PKC isoenzyme has a distinct substrate specificity. Of the many substrates of protein kinase C isoenzymes, the MARCKS proteins are highlighted as very well characterized and specific substrates of protein kinase C (review Arbuzova et al., 2002). The abbreviation MARCKS stands for myr-istoylated, alanine-rich C-kinase substrate. 

Arbuzova, A., Schmitz, A.A. and Vergeres, G. (2002) Cross-talk unfolded MARCKS proteins. Biochem.J., 362, 1-12. 

The classic example of a myristoylated protein is the MARCKS protein (myristoylated alanine-rich C kinase substrate). MARCKS is an actin filament cross-linking protein regulated by PKC and calcium-calmodulin (Aderem el al., 1988 Hartwig et al, 1992). Myristoylation of MARCKS is required for effective binding to the actin network at the plasma membrane (Thelen et al.,... 

Schmitz AAP, Pleschke JM, Kleczkowska HE et al. Poly(ADP-ribose) modulates the properties of MARCKS proteins. Biochemistry 1998 37 9520-9527. 

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