Trends in Cell Biology
ReviewADF/cofilin and actin dynamics in disease
Section snippets
Overview of ADF/cofilin activity
The mechanism by which ADF/cofilins enhance actin-filament (F-actin) dynamics is shown in Fig. 1. Actin is a polar, non-equilibrium polymer that, at steady state, has ATP–actin subunits being added at the barbed (rapidly growing) end, hydrolysis of the nucleotide and dissociation of the phosphate occurring along the filament and ADP–actin subunits dissociating from the pointed (slowly growing or shrinking) end in a process known as treadmilling. The ADF/cofilin proteins bind co-operatively to
Regulation of ADF/cofilins
ADF/cofilins in mammals are inactivated by phosphorylation on Ser3 23., 24., which does not alter the protein conformation but generates a charge repulsion that inhibits actin binding [25]. There are four kinases that have high specificity toward this serine residue: LIM kinases 1 and 2 (LIMK1 and LIMK2), and TES kinases 1 and 2 26., 27., 28.. LIM kinases are ubiquitous and lie downstream of the Rho-family GTPases, in that they can be activated by the phosphorylation of a specific threonine
Multiple actin-filament systems in cells
Along with microtubules and intermediate filaments, actin filaments have been considered by many to be a single class of cytoskeletal elements that respond uniformly to agents that perturb actin behavior in vitro. However, cells have many different populations of actin filaments, which are selected for use in a particular function through their association with other actin-binding proteins. The large family of tropomyosins (α-helical proteins that lie along the actin filament) help to specify
Actin turnover and ATP use
To understand one role of ADF/cofilins in disease processes, it is important to recognize that actin assembly and disassembly in cells is a major ATP-using process. In resting platelets (specialized enucleated cells in which macromolecular synthesis is minimal), actin dynamics were found to be responsible for up to 50% of the ATP turnover [38]. More surprisingly, in cultured primary ciliary neurons subjected to ischemia, ∼50% of the rapidly consumed ATP can be spared by blocking actin turnover
Diseases associated with ADF/cofilin and actin
For the reasons stated above, an increased incidence of altered ADF/cofilin–actin structures might be expected to occur in post-mitotic cells in which mitochondria are stressed or undergo age-related degeneration and in ischemic tissues. In rat-kidney proximal-tubule cells, cofilin undergoes dephosphorylation in response to ischemia [40]. The activated cofilin localized to the apical domain of the proximal-tubule cells, where it associated with the microvillar actin bundles [41]. Upon
ADF/cofilin and synaptic activity
Given the complexity of the upstream signaling pathways that regulate the reversible phosphorylation of ADF/cofilin, there are many sites where mutations could occur that would impact actin dynamics. Williams syndrome is a complex neurodevelopmental disorder resulting from a chromosomal deletion [50]. This chromosomal loss results in hemizygosity for several genes, one of which encodes LIMK1. The deficits associated with visuospatial cognition in Williams syndrome might be related to LIMK1 [51]
Role of ADF/cofilins in muscle development
Embryonic myoblasts produce both ADF and cofilin. When these myoblasts fuse to form myotubes, both ADF and non-muscle cofilin are downregulated, but the production of muscle cofilin is upregulated 54., 55.. Although no mutations in muscle cofilin have yet been identified in association with muscle disease in humans, loss of the muscle cofilin (unc60B) in the nematode Caenorhabditis elegans caused severe aggregation of actin in the developing body-wall muscle [56], leading to abnormal
Endothelial-cell barrier function
Many aspects of inflammation, leukocyte extravasation and metastases of cancer cells depend on the barrier function of endothelial cells [59]. Increased vascular permeability contributes to the high rate of morbidity and mortality of patients with inflammatory pulmonary diseases. Barrier integrity is enhanced through alterations in the cortical actin of the endothelial cells that strengthen the tight junctions and adherens junctions. Agents that promote the reorganization of the cortical actin
Cancer
There are at least three aspects of cancer in which ADF/cofilins and their regulation are likely to be important: the initial process of cell transformation; enhanced cell motility during metastasis; and cell division. The process of cell transformation depends on alterations in the cytoskeleton, which decrease adhesion-dependent growth. The pathway by which the viral src oncogene product (v-Src) elicits the loss of stress fibers and focal contacts has recently been elucidated [61]. This
Infertility
Evidence for a role in ADF/cofilin in regulating gametogenesis comes from studies of several different organisms. Mutations of the genes encoding ADF/cofilin in Drosophila result in sterility of both males and females [68]. Furthermore, in flies, ADF/cofilin is required for proper border-cell migration, cell-shape changes and cell rearrangements during ovary development and oogenesis. Injection of LIM kinases into Xenopus oocytes inhibits oocyte maturation [69]. This inhibition is alleviated by
Chemotaxis and activation of T cells and neutrophils
Cofilin plays an essential role in the clustering of T-cell receptors required for T-cell activation [71]. Cofilin is activated by co-stimulatory signals in T cells, and blocking its activation abolishes receptor-cap formation and T-cell proliferation, and inhibits interleukin-2 production. The chemotaxis of T cells in response to stromal-cell-derived factor 1α was shown to depend on signaling from a heterotrimeric Gi protein to Rac and then to LIMK1 and cofilin. Blockage of the cofilin
Concluding remarks
Given the central role of ADF/cofilins in regulating the turnover and reorganization of actin, it is not surprising that mutant ADF/cofilins have not turned up in genetic or proteomic screens of different diseases. Because ADF/cofilins exert no dominant-negative phenotype, mutations that do occur are likely to be recessive (loss of function). The ability of mammalian ADF or cofilin to compensate for the loss of the single yeast cofilin gene suggests that deficits in one of these gene products
Acknowledgements
We apologize to colleagues whose original contributions might not have been cited owing to lack of space. Our laboratory is supported by grants NS40371, GM35126 and NS43115 from the NIH and grant IIRG-01–2730 from the Alzheimer's Association. O.W. is supported by an INMH fellowship from the Canadian Institutes of Health Research.
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