Alternative titles; symbols
HGNC Approved Gene Symbol: CFL1
Cytogenetic location: 11q13.1 Genomic coordinates (GRCh38): 11:65,854,673-65,858,180 (from NCBI)
Cofilin is a widely distributed intracellular actin-modulating protein that binds and depolymerizes filamentous F-actin and inhibits the polymerization of monomeric G-actin in a pH-dependent manner. It is involved in the translocation of actin-cofilin complex from cytoplasm to nucleus (summary by Gillett et al., 1996).
Two cofilin isoforms have been identified in mouse: muscle, or M-type (601443) and nonmuscle, or NM-type (Ono et al., 1994). The mouse M-type cofilin is expressed in heart, skeletal muscle, and testis, whereas the NM-type is found in a wide variety of tissues, including heart and testis. NM-type cofilin expression is minimal in mature mammalian skeletal muscle. Ogawa et al. (1990) isolated a cDNA encoding a placentally expressed cofilin. Gillett et al. (1996) cloned CFL1, a nonmuscle-type cofilin, from a human promyelocytic cDNA library. The cDNA encodes a 166-amino acid polypeptide with a molecular mass of approximately 18.5 kD.
Cofilin exhibits actin-depolymerizing activity that is inhibited as a result of its phosphorylation by LIM kinase (see 601329). Maekawa et al. (1999) demonstrated that cofilin was phosphorylated during lysophosphatidic acid-induced, Rho-mediated neurite retraction. This phosphorylation was sensitive to Y-27632, a specific inhibitor of the Rho-associated kinase ROCK (601702). ROCK, which is a downstream effector of Rho, did not phosphorylate cofilin directly but phosphorylated LIM kinase, which in turn was activated to phosphorylate cofilin. Maekawa et al. (1999) concluded that phosphorylation of LIM kinase by ROCK and, consequently, increased phosphorylation of cofilin by LIM kinase, contribute to Rho-induced reorganization of the actin cytoskeleton.
Kuhn et al. (2000) reviewed evidence from studies of several avian and mammalian primary neural cultures and neuronal cell lines that showed a role for ADF and cofilin in neurite outgrowth.
To study the in vivo biochemical action of cofilin and the subsequent cellular response, Ghosh et al. (2004) used a general caging method for proteins that are regulated by phosphorylation. By acute and local activation of a chemically engineered, light-sensitive phosphocofilin mimic, they demonstrated that cofilin polymerizes actin, generates protrusions, and determines the direction of cell migration. Ghosh et al. (2004) proposed a role for cofilin that is distinct from its role as an actin-depolymerizing factor.
Yang et al. (2014) had previously found that mouse seipin (BSCL2; 606158) promotes adipogenesis to accommodate storage of excess nutrients in the form of lipids, whereas it inhibits lipid droplet production and accumulation in preadipocytes and other nonadipocyte lineages. Using mass spectrometry to identify proteins that interacted with seipin in adipose tissue lysates, Yang et al. (2014) identified the scaffold protein 14-3-3-beta (YWHAB; 601289). Interaction of seipin with 14-3-3-beta did not depend on insulin stimulation. In insulin (INS; 176730)-stimulated 3T3-L1 mouse adipocytes, 14-3-3-beta interacted with the actin-severing protein cofilin-1, and this interaction required serine phosphorylation of cofilin-1. Adipogenesis in 3T3-L1 cells was accompanied by remodeling of the actin cytoskeleton from central stress fibers to the cell cortex, concomitant with lipid droplet accumulation. Knockdown of seipin, 14-3-3-beta, or cofilin-1 in 3T3-L1 cells impaired adipocyte development and inhibited lipid drop accumulation, but stress fibers remained intact. Impaired adipogenesis was also present in 3T3-L1 cells expressing a severing-resistant actin mutant. Yang et al. (2014) concluded that the interaction of seipin with 14-3-3-beta recruits cofilin-1 to remodel the actin cytoskeleton for adipocyte differentiation.
Gillett et al. (1996) mapped CFL1 to 11q12-q13.3 by analysis of somatic cell hybrids and to 11q13 by fluorescence in situ hybridization (FISH). Fernandes et al. (1998) used FISH and mouse/hamster somatic cell hybrid analysis to map the Cfl1 gene to mouse chromosome 19.
Courseaux et al. (1996) used a combination of methods to refine maps of the approximately 5-Mb region of 11q13 that includes the MEN1 locus (131100). They proposed the following gene order: cen--PTA--FTH1--UGB--AHNAK--ROM1--MDU1--CHRM1--COX8--EMK1--FKBP2--PLCB3--[PYGM, ZFM1]--FAU--CAPN1-- [MLK3, RELA]--FOSL1--SEA--CFL1--tel.
Because deletion of n-cofilin results in embryonic lethality in mice, Bellenchi et al. (2007) used a conditional knockout approach to examine the role of n-cofilin in brain development. Homozygous mutant pups were obtained at the expected mendelian frequency, but more than 90% died within the first 3 postnatal days. The few that survived up to 30 days showed growth retardation, ataxia, and signs of epileptic seizures. Gross analysis of mutant brains revealed an overall normal organization, but the cerebral cortex had a translucent appearance and enlarged ventricles. Golgi staining of coronal sections showed that cortical layers II to IV and parts of layer V were missing in mutant brains. Studies performed on cultured cortical neuronal progenitors revealed that loss of n-cofilin impaired their radial migration. Neuronal progenitors in the ventricular zone showed increased cell cycle exit and exaggerated neuronal differentiation, leading to depletion of the neuronal progenitor pool.
Bellenchi, G. C., Gurniak, C. B., Perlas, E., Middei, S., Ammassari-Teule, M., Witke, W. N-cofilin is associated with neuronal migration disorders and cell cycle control in the cerebral cortex. Genes Dev. 21: 2347-2357, 2007. [PubMed: 17875668] [Full Text: https://doi.org/10.1101/gad.434307]
Courseaux, A., Grosgeorge, J., Gaudray, P., Pannett, A. A. J., Forbes, S. A., Williamson, C., Bassett, D., Thakker, R. V., Teh, B. T., Farnebo, F., Shepherd, J., Skogseid, B., Larsson, C., Giraud, S., Zhang, C. X., Salandre, J., Calender, A. Definition of the minimal MEN1 candidate area based on a 5-Mb integrated map of proximal 11q13. Genomics 37: 354-365, 1996. [PubMed: 8938448]
Fernandes, M., Poirier, C., Lespinasse, F., Carle, G. F. The mouse homologs of human GIF, DDB1, and CFL1 genes are located on chromosome 19. Mammalian Genome 9: 339-342, 1998. [PubMed: 9530637] [Full Text: https://doi.org/10.1007/s003359900763]
Ghosh, M., Song, X., Mouneimne, G., Sidani, M., Lawrence, D. S., Condeelis, J. S. Cofilin promotes actin polymerization and defines the direction of cell motility. Science 304: 743-746, 2004. [PubMed: 15118165] [Full Text: https://doi.org/10.1126/science.1094561]
Gillett, G. T., Fox, M. F., Rowe, P. S. N., Casimir, C. M., Povey, S. Mapping of human non-muscle type cofilin (CFL1) to chromosome 11q13 and muscle-type cofilin (CFL2) to chromosome 14. Ann. Hum. Genet. 60: 201-211, 1996. [PubMed: 8800436] [Full Text: https://doi.org/10.1111/j.1469-1809.1996.tb00423.x]
Kuhn, T. B., Meberg, P. J., Brown, M. D., Bernstein, B. W., Minamide, L. S., Jensen, J. R., Okada, K., Soda, E. A., Bamburg, J. R. Regulating actin dynamics in neuronal growth cones by ADF/cofilin and Rho family GTPases. J. Neurobiol. 44: 126-144, 2000. [PubMed: 10934317]
Maekawa, M., Ishizaki, T., Boku, S., Watanabe, N., Fujita, A., Iwamatsu, A., Obinata, T., Ohashi, K., Mizuno, K., Narumiya, S. Signaling from Rho to the actin cytoskeleton through protein kinases ROCK and LIM-kinase. Science 285: 895-898, 1999. [PubMed: 10436159] [Full Text: https://doi.org/10.1126/science.285.5429.895]
Ogawa, K., Tashima, M., Yumoto, Y., Okuda, T., Sawada, H., Okuma, M., Maruyama, Y. Coding sequence of human placenta cofilin cDNA. Nucleic Acids Res. 18: 7169 only, 1990. [PubMed: 2263493] [Full Text: https://doi.org/10.1093/nar/18.23.7169]
Ono, S., Minami, N., Abe, H., Obinata, T. Characterization of a novel cofilin isoform that is predominantly expressed in mammalian skeletal muscle. J. Biol. Chem. 269: 15280-15286, 1994. [PubMed: 8195165]
Yang, W., Thein, S., Wang, X., Bi, X., Ericksen, R. E., Xu, F., Han, W. BSCL2/seipin regulates adipogenesis through actin cytoskeleton remodelling. Hum. Molec. Genet. 23: 502-513, 2014. [PubMed: 24026679] [Full Text: https://doi.org/10.1093/hmg/ddt444]