Disease relevance of CFL1

• CONCLUSION: The sequence variation of human CFL1 gene is a genetic modifier for spina bifida risk in this California population [1].
• Cofilin was phosphorylated in N1E-115 neuroblastoma cells during lysophosphatidic acid-induced, Rho-mediated neurite retraction [2].
• Our data provide evidence of a novel role of LIMK1 in regulating cell division and invasive property of prostate cancer cells and indicate that the effect is not mediated by phosphorylation of cofilin [3].
• Surprisingly, co-expression of constitutive active ADF and cofilin prevented efficient Salmonella entry, whereas expression of either one alone had no effect [4].
• In this study, we found that over-expression of cofilin led to increased radiation sensitivity in human non-small lung cancer H1299 cells [5].

Psychiatry related information on CFL1

• However, we could detect no difference in the levels of expression of either ADF or cofilin in the hippocampal tissue from normal individuals and Alzheimer's disease patients [6].
• Two standardized neuropsychological word-generation tasks (controlled word-association tests: CFL and Animals) were then administered (4 minutes total) followed again by the two baseline procedures [7].
• Participants completed neuropsychological testing with the Dementia Rating Scale (DRS), Logical Memory, and CFL Word Fluency. There were no significant demographic group differences, although seniors with epilepsy had higher self-reported depression [8].

High impact information on CFL1

• Furthermore, SSH and the hSSHs dephosphorylated P cofilin in cultured cells and in cell-free assays [9].
• In Drosophila, loss of ssh function dramatically increased levels of both F actin and phospho-cofilin (P cofilin) and disorganized epidermal cell morphogenesis [9].
• Destrin is an isoprotein of cofilin that regulates actin cytoskeleton in various eukaryotes [10].
• When expressed in cultured cells, LIMK-1 induces actin reorganization and reverses cofilin-induced actin depolymerization [11].
• Cofilin is known to be a potent regulator of actin filament dynamics, and its ability to bind and depolymerize actin is abolished by phosphorylation of serine residue at 3; however, the kinases responsible for this phosphorylation have not been identified [11].

Chemical compound and disease context of CFL1

• Once activated, the diffuse cytoplasmic distribution of the actin depolymerizing factor/cofilin protein relocalizes to the luminal membrane blebs [12].
• Prohibitin and Cofilin Are Intracellular Effectors of Transforming Growth Factor {beta} Signaling in Human Prostate Cancer Cells [13].
• In malignant T lymphoma cells, dephosphorylation and nuclear translocation of pp19/cofilin occur spontaneously through constitutive activation of a serine phosphatase [14].
• Cofilin is normally rephosphorylated when platelets are stimulated in the presence of Arg-Gly-Asp-Ser (RGDS) peptide or wortmannin to block alpha(IIb)beta3 cross-linking and signaling or in platelets isolated from a patient with Glanzmann thrombasthenia, which express only 2-3% of normal alpha(IIb)beta3 levels [15].
• In addition, CFL was more effective than fosfomycin against "difficult" Gram-negative bacteria such as Proteus spp. and Pseudomonas aeruginosa [16].

Biological context of CFL1

• BACKGROUND: CFL1 encodes human non-muscle cofilin (n-cofilin), which is an actin-depolymerizing factor and is essential in cytokinesis, endocytosis, and in the development of all embryonic tissues [1].
• We hypothesized that genetic variation within the human CFL1 gene may alter the protein's function and result in defective actin depolymerizing and cellular activity during neural tube closure [1].
• METHODS: Having re-sequenced the human CFL1 gene and identified five common single nucleotide polymorphisms (SNPs) in our target population, we investigated whether there existed a possible association between the genetic variations of the CFL1 gene and risk of spina bifida [1].
• Cofilin mediates lamellipodium extension and polarized cell migration by accelerating actin filament dynamics at the leading edge of migrating cells [17].
• Two counteracting pathways, a cofilin phosphatase and LIMK-1, are activated during platelet aggregation/secretion regulating cofilin phosphorylation sequentially and independently of integrin alpha(IIb)beta(3) engagement [18].

Anatomical context of CFL1

• Phosphorylation of cofilin by overexpressing LIM kinase 1 resulted in a stabilization of the actin cytoskeleton [19].
• Cofilin interacts with ClC-5 and regulates albumin uptake in proximal tubule cell lines [19].
• Like TESK1, TESK2 phosphorylated cofilin specifically at Ser-3 and induced formation of actin stress fibers and focal adhesions [20].
• The interaction of cofilin with triose-phosphate isomerase as well as Na,K-ATPase was confirmed by immunoprecipitation and confocal microscopy in HeLa cells [21].
• Cofilin phosphorylation by protein kinase testicular protein kinase 1 and its role in integrin-mediated actin reorganization and focal adhesion formation [22].

Associations of CFL1 with chemical compounds

• LIMK-1 phosphorylation and cofilin dephosphorylation and rephosphorylation during aggregation were independent of integrin alpha(IIb)beta(3) engagement [18].
• Ouabain-sensitive (86)Rb(+) uptake showed that Na,K-ATPase activity was increased by the overexpression of cofilin and lysophosphatidic acid treatment, but not by the overexpression of mutant cofilin S3A and Y-27632 treatment [21].
• Pretreatment with the glycolytic inhibitor iodoacetic acid caused a remarkable reduction of Na,K-ATPase activity, whereas pretreatment with the oxidative inhibitor carbonyl cyanide m-chlorophenylhydrazone caused no detectable changes, suggesting that the phosphorylated cofilin is involved in feeding glycolytic fuel for Na,K-ATPase activity [21].
• Importantly, knockdown of SSH1L expression by RNA interference abolished A23187- or calcineurin-induced cofilin dephosphorylation [23].
• Phosphoinositide 3-kinase-mediated activation of cofilin phosphatase Slingshot and its role for insulin-induced membrane protrusion [24].

Physical interactions of CFL1

• We demonstrated that dual regulation of cyclic AMP and Ca2+ determines cofilin (an actin-binding protein) phosphorylation states and LIM kinase 1 (a cofilin kinase) expression level during neuritogenesis [25].
• These results are consistent with a model in which pH-dependent motion of subdomain 1 relative to subdomain 2 (through region 75-105) of actin reveals a second cofilin binding site on actin (centered around region 112-125) that allows ADF/cofilin association with the actin filament [26].

Enzymatic interactions of CFL1

• Surprisingly, during shape change cofilin phosphorylation was unaltered, and during aggregation/secretion cofilin was first rapidly dephosphorylated by an okadaic acid-insensitive phosphatase and then slowly rephosphorylated by LIMK-1 [18].
• These results suggest that SSH1 plays a critical role in cytokinesis by dephosphorylating and reactivating cofilin in later stages of mitosis [27].
• Like LIM-kinases, TESK1 phosphorylated cofilin specifically at Ser-3, both in vitro and in vivo [22].
• Further, we examined the localization of the phosphorylated form of cofilin using phospho-specific antibody raised against phosphorylated cofilin [28].
• CIN directly dephosphorylates cofilin with high specificity and colocalizes with cofilin in motile and dividing cells [29].

Regulatory relationships of CFL1

• These findings suggest that LIMK1 and SSH1 play critical roles in controlling growth cone motility and morphology and neurite extension by regulating the activity of cofilin and may be involved in signaling pathways that regulate stimulus-induced growth cone guidance [30].
• Par-3 mediates the inhibition of LIM kinase 2 to regulate cofilin phosphorylation and tight junction assembly [31].
• A role of LIM kinase 1/cofilin pathway in regulating endocytic trafficking of EGF receptor in human breast cancer cells [32].
• A pathway of neuregulin-induced activation of cofilin-phosphatase Slingshot and cofilin in lamellipodia [33].
• Furthermore, dominant negative LIMK1 and a mutant cofilin inhibited the specific cytoskeletal and cell shape changes that were induced in response to a recently characterized constitutively activated PAK4 mutant [34].

Other interactions of CFL1

• Cofilin phosphorylation by LIM-kinase 1 and its role in Rac-mediated actin reorganization [11].
• Although 72% identical in sequence, ADF has a much higher depolymerizing activity than cofilin at pH 8 [35].
• Co-expression of cofilin rescued the inhibitory effect of phosphatase-inactive SSH1 on cytokinesis [27].
• Par-3 inhibits LIMK2 activity in vitro, and overexpressed Par-3 suppresses cofilin phosphorylation that is induced by lysophosphatidic acid [31].
• We further analyzed the effect of S3A cofilin mutant on EGFR trafficking, and found an efficient delivery of Texas red-EGF into late endosomes/lysosomes at 15-30 min after internalization [32].

Analytical, diagnostic and therapeutic context of CFL1

• Expression of non-phosphorylatable mutant cofilin proteins in NIH3T3 cells and determination of their subcellular localization by confocal laser scanning microscopy reveal that non-phosphorylated cofilin accumulates within nuclei [36].
• Filaments of cofilin-decorated TMR-actin and unlabeled actin are indistinguishable, as revealed by electron microscopy and three-dimensional reconstruction [37].
• The de-phosphorylation of cofilin-1 was confirmed using western blotting of UV-exposed skin equivalents and ex vivo skin protein extracts [38].
• These two proteins were identified as the phosphorylated and non-phosphorylated forms of the pH-sensitive actin-depolymerizing protein, cofilin, by sequencing of peptide fragments and immunoblotting with a monoclonal antibody specific for cofilin [39].
• To determine whether the DNA repair capacity was altered in cofilin over-expressing cells, comet assays were performed on irradiated cells [5].

References