Disease relevance of Cfl1

• Since p17a and p17b were predominant forms even in nonstimulated cells, peptides were generated from them with Staphylococcus aureus V8 protease or cyanogen bromide; subsequent sequencing of these peptides and homology search allowed identification of p17a and p17b as destrin- and cofilin-like proteins, respectively [1].
• Ribosomal protein S18 identified as a cofilin-binding protein by using phage display library [2].
• The activity status of cofilin is directly related to invasion, intravasation, and metastasis of mammary tumors [3].
• Different actin-binding proteins can change this length; it is reduced markedly by cofilin binding, or can increase to 38.5 nm in the abnormally large nemaline myopathy Z-band [4].
• The active form is inferred to be more peripherally localised and to be present in apoptotic blebs, since an antibody specific for phosphorylated cofilin did not stain the cell periphery nor apoptotic blebs [5].

High impact information on Cfl1

• A role for calcium-dependent actin depolymerization in LTD of NMDAR EPSCs was supported by the findings that the actin stabilizer phalloidin and a cofilin inhibitory peptide each blocked LTD of NMDAR EPSCs but not AMPAR EPSCs [6].
• This increase in F-actin content is dependent on NMDA receptor activation and involves the inactivation of actin depolymerizing factor/cofilin [7].
• Cofilin, a LIMK1 substrate, is essential for the regulation of actin polymerization and depolymerization during cell migration [3].
• LIMK1-mediated decreases or increases in the activity of the cofilin pathway are shown to cause proportional decreases or increases in motility, intravasation, and metastasis of tumor cells [3].
• Molecular mechanisms of invadopodium formation: the role of the N-WASP-Arp2/3 complex pathway and cofilin [8].

Biological context of Cfl1

• Therefore, our results demonstrate that the early PLC and cofilin-dependent barbed end transient is required for the initiation of protrusions and is involved in setting the direction of cell movement in response to EGF [9].
• Suppression of cofilin, using either small interfering RNA silencing or function-blocking antibodies, selectively inhibits the early transient [9].
• Our results suggest that the presence of actin in the nucleus may be required for certain stress-induced responses and that cofilin is essential for the nuclear import of actin [10].
• Complete amino acid sequences and phosphorylation sites, determined by Edman degradation and mass spectrometry, of rat parotid destrin- and cofilin-like proteins [11].
• We previously reported that an actin-binding protein, cofilin, is involved in superoxide production, phagocytosis, and chemotaxis in activated phagocytes through cytoskeletal reorganization [2].

Anatomical context of Cfl1

• Latrunculin B or ATP depletion induces cofilin-dependent translocation of actin into nuclei of mast cells [10].
• In addition, GeneChip microarrays (Affymetrix, Santa Clara, CA) were utilized to determine the abundance of mRNA for all cofilin isoforms in Sertoli cells [12].
• Non-muscle cofilin is a component of tubulobulbar complexes in the testis [12].
• Cofilin, a calcium-independent actin-depolymerizing protein, previously has been identified in the testis, but has not been localized to specific structures in the seminiferous epithelium [12].
• Beta-adrenergic or cholinergic stimulation of the rat parotid gland was earlier shown to induce dephosphorylation of endogenous destrin- and cofilin-like proteins, which are phosphorylated in resting cells at Ser residues probably present near the N-terminals [11].

Associations of Cfl1 with chemical compounds

• In permeabilized cells, the appearance of nuclear actin and cofilin was not significantly affected by increasing [Ca(2+)] and/or adding guanosine 5'-O-(3-thiotriphosphate), but was greatly promoted when ATP was withdrawn [10].
• Earlier work had shown that partial cleavage of the phosphorylated destrin- and cofilin-like proteins with cyanogen bromide provides unphosphorylated 16.7- and 18.3-kDa fragments, respectively [11].
• Moreover, treatment of cells with 10% dimethyl sulfoxide also caused the dephosphorylation of cofilin [13].
• Cofilin is a widely distributed 21-kDa actin-modulating protein that forms intranuclear actin/cofilin rods in cultured fibroblastic cells exposed to heat shock or 10% dimethyl sulfoxide [13].
• In this study, cofilin was shown to be phosphorylated on a serine residue in cultured rat fibroblastic 3Y1 cells [13].

Regulatory relationships of Cfl1

• The obtained data are consistent with the idea that ROS up-regulation mediates two key events in Ras-induced morphological transformation and cell motility: it is responsible for Rac1 activation and is necessary (though insufficient) for realization of Ras-induced cofilin dephosphorylation [14].
• Inhibition of MEK using U0126 prevented v-Src-induced disruption of the cytoskeleton as well as dephosphorylation of cofilin, whereas treatment with a phosphatidylinositol 3-kinase inhibitor had no protective effect [15].

Other interactions of Cfl1

• Y-27632 (10 micromol/l; 1 h pretreatment), an inhibitor of Rho-associated coiled-coil-containing protein kinases (ROCK), prevented ET- and caPKC epsilon-induced FAK activation as well as cofilin phosphorylation [16].
• A decrease in the phosphorylation level of cofilin was detected upon v-Src activation, which is indicative of attenuated Rho function [15].
• In addition to alpha-smooth-muscle actin, these structures contain cytoplasmic actins, gelsolin and cofilin but not other major actin-binding proteins [17].
• Decreased abundance was also observed for cofilin 1, a protein linked to tumorigenesis, and for the GRP 75 precursor and preproalbumin, both of which are responsive to oxidative stress and/or inflammation [18].
• The analysis of enriched mitochondrial fractions identified 10 proteins including sodium/potassium-transporting ATPase, cofilin, dihydropyrimidinase, pyruvate kinase and voltage dependent anion channel 1 that were statistically significantly (P < 0.05) altered in Abeta-treated cultures [19].

Analytical, diagnostic and therapeutic context of Cfl1

• On one-dimensional (1D) Western blots this antibody reacted monospecifically with one band, and on 2D blots reacted with two dots, which we interpret as phosphorylated and nonphosphorylated forms of a single cofilin isotype [12].
• To determine if cofilin is found in Sertoli cells and is concentrated at actin-rich structures, we reacted fixed frozen sections of rat testis, fixed fragmented tissue, and blots of seminiferous epithelium with pan-specific and non-muscle cofilin antibodies [12].
• Two-dimensional gel electrophoresis revealed that about 50% of the cofilin was phosphorylated in 3Y1 cells at 37 degrees C. Exposure of the cells to heat shock at 43 degrees C induced dephosphorylation of cofilin [13].
• Although no exogenous protein phosphatases tested dephosphorylated cofilin in the homogenate, the cofilin that was isolated by immunoprecipitation was clearly dephosphorylated by protein phosphatases 1, 2A, and 2C [20].
• Subsequent testing in cell cultures revealed that the CDK5 inhibitor blocked mitochondrial translocation of pro-apoptotic cofilin in cerebellar granule neurons and enhanced neurite outgrowth in dorsal root ganglia [21].

References