Disease relevance of Marcksl1

• MRP depletion was not obtained with other phagocytic stimuli including zymosan, latex beads, or heat-killed Streptococcus mitis, a Gram-positive bacterium [1].
• Nonetheless, the identification of linked and neighboring polymorphisms for MACS and MLP should permit similar genetic studies in other groups of patients with neural tube defects and other neurodevelopmental abnormalities [2].
• Inhibition of mucin secretion with MARCKS-related peptide improves airway obstruction in a mouse model of asthma [3].
• Intratracheal administration of this MARCKS-related peptide could therapeutically reduce mucus secretion in the airways of human patients with asthma, chronic bronchitis and cystic fibrosis [4].
• Disruption of the MacMARCKS gene prevents cranial neural tube closure and results in anencephaly [5].

High impact information on Marcksl1

• We report here on MacMARCKS, a MARCKS homolog, whose synthesis is dramatically increased in macrophages when these cells are exposed to bacterial lipopolysaccharide [6].
• CONCLUSIONS: Overexpression of Mrp 3 and Mrp 4 in CBDL mice is FXR independent and could play an important role in the adaptive hepatic ABC transporter response to cholestasis [7].
• Neural tube defects and abnormal brain development in F52-deficient mice [8].
• F52 is a myristoylated, alanine-rich substrate for protein kinase C. We have generated F52-deficient mice by the gene targeting technique [8].
• This suggests a central role for MacMARCKS and the PKC signal transduction pathway in the folding of the anterior neural plate during the early phases of brain formation, and supports the hypothesis that actin-based motility directs cranial neural tube closure [5].

Biological context of Marcksl1

• Five related loci were labeled Mrp-rs1 through Mrp-rs5 (for Mrp-related sequences) and were mapped to mouse chromosomes 10, 17, 15, 13, and X, respectively [9].
• Nucleotide sequence, expression, and chromosomal mapping of Mrp and mapping of five related sequences [9].
• When the plasmid containing the genomic sequences was transfected into fibroblasts lacking endogenous Mrp expression, the 407 bp of promoter conferred high-level expression of the full-length, spliced mRNA [9].
• Phosphorylation of MARCKS and MRP by PKC disrupted the protein-calmodulin complexes, with half-lives of 4.0 and 3.5 min, respectively [10].
• Down-regulation of MARCKS-related protein (MRP) in macrophages infected with Leishmania [1].

Anatomical context of Marcksl1

• Activation of murine macrophages by cytokines increased MRP expression as determined by Western blot analysis [1].
• Since only a marginal binding could be observed with neutral phosphatidylcholine vesicles, we propose that electrostatic interactions are the major determinant of the binding of MRP to pure lipid membranes [11].
• MLP was localized to chromosome 1p34-->1pter by analysis of human-mouse somatic cell hybrid DNA and to 1p34 by fluorescence in situ hybridization [2].
• Recent studies using gene disruption in vivo have demonstrated the importance of both MARCKS and MLP to the development of the central nervous system; specifically, mice lacking either protein exhibit a high frequency of neural tube defects [2].
• Our results suggest that MARCKS and MRP may play important roles in microglia activated by amyloid peptides [12].

Associations of Marcksl1 with chemical compounds

• The partition coefficient, Kp, describing the affinity of myristoylated MRP for acidic lipid vesicles (20% phosphatidylserine, 80% phosphatidylcholine) is 5-8 x 10(3) M-1, which is only 2-4 times larger than the partition coefficient for the unmyristoylated protein [11].
• MacMARCKS and MARCKS also share a second, highly conserved region also found in the internalization domain of the mannose-6-phosphate receptor [6].
• We report here that macrophage-enriched myristoylated alanine-rich C kinase substrate (MacMARCKS), a membrane-associated PKC substrate involved in integrin activation, is required for this PKC-stimulated diffusion of integrin molecules [13].
• MacMARCKS contains within it a basic effector domain that contains the serine residues that are phosphorylated by protein kinase C, as well as a calcium/calmodulin and actin-binding site [14].
• Lipopolysaccharide- and PMA-activated macrophages from mice fed the trimyristin diet had significantly greater levels of MacMARCKS than LPS- and PMA-activated macrophages of mice fed the safflower oil-containing diet [15].

Physical interactions of Marcksl1

• MARCKS-related protein binds to actin without significantly affecting actin polymerization or network structure. Myristoylated alanine-rich C kinase substrate [16].
• The F52 peptide also bound calmodulin with high affinity (Kd = less than 3 nM); this binding could be disrupted by phosphorylation of the peptide with PKC, with a half-time of 8 min [17].

Other interactions of Marcksl1

• Mrp mapped to a position on mouse chromosome 4 that was closely linked to the Lck locus [9].
• Interestingly, the affinity of MRP for acidic lipid membranes is 20-30-fold smaller than reported for murine MARCKS (Kim, J., Shishido, T., Jiang, X., Aderem, A. A., and McLaughlin, S. (1994) J. Biol. Chem. 269, 28214-28219) [11].
• The kinetics of PKC-mediated phosphorylation and the calmodulin binding properties of intact, recombinant MARCKS and MRP were investigated and compared with previous studies of synthetic peptides spanning the PKC phosphorylation site/calmodulin binding domains (PSCBD) of these proteins [10].
• Staurosporine also suppresses the TPA-induced down-regulation, possibly indicating that the down-regulation of the MARCKS-related protein is dependent on its phosphorylation by protein kinase C [18].
• The F52 protein also was myristoylated in E. coli by co-expression with N-myristoyltransferase [17].

Analytical, diagnostic and therapeutic context of Marcksl1

• Ultracentrifugation and circular dichroic spectroscopy reveal that MRP is an elongated protein, with an axis ratio estimated between 7 and 12 and with an apparent random coil conformation [19].
• Leishmania-dependent MRP depletion was confirmed by [3H]myristate labeling and by immunofluorescence microscopy [1].
• Sequence analysis of tryptic phosphopeptides revealed that the first and third, but not the second, serines in the MRP PSCBD were phosphorylated by PKC [10].
• This 433-bp fragment drove expression of an MLP-beta-galactosidase transgene in a tissue-specific and developmental expression pattern that was similar to that observed for the endogenous gene, as shown by in situ hybridization histochemistry [2].
• Radiation hybrid mapping of MLP placed it between genetic markers D1S511 (LOD > 3.0) and WI9232 [2].

References