Disease relevance of Marcks

• Anoxia followed by 30 min normoxia enhanced MARCKS phosphorylation in the membrane but not in the cytosolic fraction [1].
• The A beta (25-35)-induced phosphorylation of MARCKS was inhibited by pretreatment with the tyrosine kinase inhibitors genistein and herbimycin A, but not with pertussis toxin [2].
• Phosphopeptide maps of either the 83 or 85 kDa proteins were generated with Staphylococcus aureus V8 protease and revealed 13 and 9 kDa phosphopeptides, which are characteristic of the authentic MARCKS protein [3].
• Brain protein kinase C assay using MARCKS substrate reveals no translocation due to profound insulin-induced hypoglycemia [4].
• Addition of [gamma-32P]ATP to the membrane fraction of digitonin-permeabilized C6 glioma cells resulted in phosphorylation and release of MARCKS, indicating involvement of an active membrane-bound kinase [5].

Psychiatry related information on Marcks

• The data suggest that a biphasic modulation of protein kinase C and MARCKS by Abeta(1-40) combined with anoxic stress may play a role in Alzheimer's disease pathology [1].

High impact information on Marcks

• Essential role for the PKC target MARCKS in maintaining dendritic spine morphology [6].
• MARCKS associates with membranes via the combined action of myristoylation and a polybasic effector domain, which binds phospholipids and/or F-actin, unless phosphorylated by PKC [6].
• We investigated the role of MARCKS (myristoylated, alanine-rich C-kinase substrate) in dendrites of 3-week-old hippocampal cultures [6].
• Furthermore, depletion of MARCKS by MARCKS-AON treatment of neurons resulted in a significant decrease in Ang II-stimulated accumulation of TH and DbetaH immunoreactivities and [3H]NE uptake activity in synaptosomes [7].
• These observations demonstrate that phosphorylation of MARCKS by PKCbeta and its redistribution from varicosities to neurites is important in Ang II-induced synaptic accumulation of TH, DbetaH, and NE [7].

Biological context of Marcks

• On the other side, proteins affecting signal transduction and cytoskeleton-related proteins (heterotrimeric G-proteins, protein kinase C, MARCKS, tubulin), were not enriched within detergent-resistant fractions during cell differentiation, but were recovered within this fraction in mature neurons [8].
• These results suggest that MARCKS is a target of PKG, and PKG-dependent phosphorylation of MARCKS results in its degradation to reduce its protein levels in the cells [9].
• In addition, possible degradation products of MARCKS were observed after transfection of PKG or stimulation with 8pCPT-cGMP [9].
• However, cells expressing MARCKS ED mutants were irregularly shaped and stress fibers were either shorter or less abundant, and cell adhesion and viability were not affected [10].
• Like control cells, those expressing wild type MARCKS were elongated and possessed longitudinally oriented stress fibers, although these cells were more prone to detach from the substratum and undergo cell death upon phorbol ester treatment [10].

Anatomical context of Marcks

• Cathepsin B-like proteolysis and MARCKS degradation in sub-lethal NMDA-induced collapse of dendritic spines [11].
• Together these data suggest a model in which NMDA-induced spine collapse involves cathepsin B-like proteolysis of MARCKS, and possibly other proteins that regulate the actin-based cytoskeleton [11].
• It involves activation of protein kinase C (PKC)beta subtype and phosphorylation and redistribution of myristoylated alanine-rich C kinase substrate (MARCKS) in neurites [7].
• These data indicate that eicosanoid-mediated repellent effects result from the direct and selective activation of PKCepsilon and suggest the involvement of myristoylated alanine-rich protein kinase C substrate phosphorylation in growth cone collapse [12].
• Glucose-induced phosphorylation of myristoylated alanine-rich C kinase substrate (MARCKS) in isolated rat pancreatic islets [13].

Associations of Marcks with chemical compounds

• Ang II caused a dramatic redistribution of MARCKS from neuronal varicosities to neurites [7].
• Regulation of angiotensin II-induced neuromodulation by MARCKS in brain neurons [7].
• Characterization of the phosphatidylserine-binding region of rat MARCKS (myristoylated, alanine-rich protein kinase C substrate). Its regulation through phosphorylation of serine 152 [14].
• In 32P-labeled hippocampal neurons, exposure to 10 microM glutamate induced a long lasting increase in phosphorylation of MARCKS [15].
• In islets exposed to G20 + 50 nM staurosporine, MARCKS phosphorylation was inhibited by 90 +/- 4% compared with control islets exposed to 20 mM glucose alone [13].

Physical interactions of Marcks

• Inhibitors of actin polymerization and calmodulin binding enhance protein kinase C-induced translocation of MARCKS in C6 glioma cells [16].

Enzymatic interactions of Marcks

• CaM and S100 inhibited the PKM-catalyzed phosphorylation of MARCKS only in the presence of Ca2+ and addition of phosphatidylserine (PS)/dioleoylglycerol (DG) did not influence the inhibitory effect [17].

Regulatory relationships of Marcks

• Differential activities of PKC were also observed in synaptosol and in intact synaptosomes where PMA stimulated phosphorylation of MARCKS, but not dephosphin [18].
• Investigations of the functional properties also showed that the MARCKS phosphorylation by MAP kinase regulates its calmodulin-binding ability and its interaction with F-actin as seen in the PKC-dependent phosphorylation [15].
• Endothelin-1 stimulates myristoylated alanine-rich C-kinase substrate (MARCKS) phosphorylation in rat cerebellar slices [19].

Other interactions of Marcks

• On the contrary, all Fyn and almost all MARCKS remained in the supernatant [20].
• TRH stimulates the release of MARCKS from the membrane/cytoskeletal fraction to the cytosol fraction [21].
• Incubation of neurons with PKCbeta subtype specific antisense oligonucleotide (AON) significantly attenuated both redistribution and phosphorylation of MARCKS [7].
• Of these three agonists, only TPA stimulated phosphorylation of MARCKS (225% of control), a specific substrate of PKC [22].
• These results suggest that glutamate causes a long lasting increase in MARCKS phosphorylation through activation of the N-methyl-D-aspartate receptor and subsequent activation of MAP kinase in the hippocampal neurons [15].

Analytical, diagnostic and therapeutic context of Marcks

• Western blot analysis showed that the MARCKS protein levels were decreased when the cells were stimulated with 8pCPT-cGMP [9].
• After stimulation, the homogenized islets were processed by immunoprecipitation with a specific polyclonal anti-MARCKS antibody, followed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis [13].
• The phosphopeptide mapping and immunoblotting analyses confirmed that PKC-dependent phosphorylation of MARCKS was transient and the MAP kinase-dependent phosphorylation was relatively persistent [15].
• Compared with R6-C1 cells, R6-PKC3 cells exhibited a 2-3-fold increase in the basal level of phosphorylation of MARCKS and after treatment with TPA, displayed a dramatic prolongation in phosphorylation of this protein [23].
• RESULTS: RT-PCR analysis of 80K/MARCKS mRNA in neonatal (2-day) and adult (42-day) cardiac myocytes showed the expression of this gene in both cell types [24].

References