ADF/cofilin and actin dynamics in disease

doi:10.1016/S0962-8924(02)02404-2

Trends in Cell Biology

Volume 12, Issue 12, 1 December 2002, Pages 598-605

https://doi.org/10.1016/S0962-8924(02)02404-2 Get rights and content

Abstract

ADF/cofilins are key regulators of actin dynamics in normal cells. Recent findings suggest that, under cellular stress, the wild-type proteins might form complexes with actin that can alter cell function. Owing to their rapid formation, these complexes might initiate or aid in the progression of diseases as diverse as Alzheimer's disease and ischemic kidney disease. Although evidence for their involvement in diseases other than Alzheimer's and ischemic kidney disease is tenuous, recent studies suggest that altered production, regulation or localization of these proteins might lead to cognitive impairment, inflammation, infertility, immune deficiencies and other pathophysiological defects.

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.

References (75)

B. Ilkovski
Nemaline myopathy caused by mutations in the muscle alpha-skeletal actin gene
Am. J. Hum. Genet.
(2001)
S.K. Maciver et al.
Actophorin preferentially binds monomeric ADP–actin over ATP-bound actin: consequences for cell locomotion
FEBS Lett.
(1994)
J. Condeelis
How is actin polymerization nucleated in vivo?
Trends Cell Biol.
(2001)
S. Yeoh
Determining the differences in actin binding by human ADF and cofilin
J. Mol. Biol.
(2002)
K. Zhao
Rapid and phosphoinositol-dependent binding of the SWI/SNF-like BAF complex to chromatin after T lymphocyte receptor signaling
Cell
(1998)
B.J. Agnew
Reactivation of phosphorylated actin depolymerizing factor and identification of the regulatory site
J. Biol. Chem.
(1995)
L. Blanchoin
Phosphorylation of Acanthamoeba actophorin (ADF/cofilin) blocks interaction with actin without a change in atomic structure
J. Mol. Biol.
(2000)
O. Rosok
Identification and characterization of TESK2, a novel member of the LIMK/TESK family of protein kinases, predominantly expressed in testis
Genomics
(1999)
C. Dan
Cytoskeletal changes regulated by the PAK4 serine/threonine kinase are mediated by LIM kinase 1 and cofilin
J. Biol. Chem.
(2001)
J. Toshima
Cell-type-specific expression of a TESK1 promoter-linked lacZ gene in transgenic mice
Biochem. Biophys. Res. Commun.
(2001)

A. Gohla et al.

14-3-3 regulates actin dynamics by stabilizing phosphorylated cofilin

Curr. Biol.

(2002)

R. Niwa

Control of actin reorganization by slingshot, a family of phosphatases that dephosphorylate ADF/cofilin

Cell

(2002)

J. Pfannstiel

Human cofilin forms oligomers exhibiting actin bundling activity

J. Biol. Chem.

(2001)

C. Behl

Hydrogen peroxide mediates amyloid β protein toxicity

Cell

(1994)

U. Bellugi

Bridging cognition, the brain and molecular genetics: evidence from Williams syndrome

Trends Neurosci.

(1999)

Y. Meng

Abnormal spine morphology and enhanced LTP in LIMK-1 knockout mice

Neuron

(2002)

S. Ono

Characterization of a novel cofilin isoform that is predominantly expressed in mammalian skeletal muscle

J. Biol. Chem.

(1994)

G. Pawlak et al.

MEK mediates v-Src-induced disruption of the actin cytoskeleton via inactivation of the Rho–ROCK–LIM kinase pathway

J. Biol. Chem.

(2002)

H. Chen

Regulating actin-filament dynamics in vivo

Trends Biochem. Sci.

(2000)

I. Ichetovkin

Cofilin produces newly polymerized actin filaments that are preferred for dendritic nucleation by the Arp2/3 complex

Curr. Biol.

(2002)

T. Amano

Mitosis-specific activation of LIM motif-containing protein kinase and roles of cofilin phosphorylation and dephosphorylation in mitosis

J. Biol. Chem.

(2002)

T. Takahashi

Functional involvement of Xenopus LIM kinases in progression of oocyte maturation

Dev. Biol.

(2001)

H. Takahashi

Impaired spermatogenic ability of testicular germ cells in mice deficient in the LIM-kinase 2 gene

Dev. Biol.

(2002)

T. Kakunaga

A mutation in actin associated with neoplastic transformation

Fed. Proc.

(1984)

P. Lappalainen

The ADF homology (ADF-H) domain: a highly exploited actin-binding module

Mol. Biol. Cell

(1998)

J.R. Bamburg

Proteins of the ADF/cofilin family: essential regulators of actin dynamics

Annu. Rev. Cell Dev. Biol.

(1999)

M.K. Vartiainen

The three mouse ADF/cofilins evolved to fulfill cell-specific requirements for actin dynamics

Mol. Biol. Cell

(2002)

A.L. Moon

Cofilin is an essential component of the yeast cortical cytoskeleton

J. Cell Biol.

(1993)

K. Iida

Isolation of a yeast essential gene, COF1, that encodes a homologue of mammalian cofilin, a low-M_r actin-binding and depolymerizing protein

Gene

(1993)

P. Lappalainen et al.

Cofilin promotes rapid actin filament turnover in vivo

Nature

(1997)

T.M. Svitkina et al.

Arp2/3 complex and actin depolymerizing factor/cofilin in dendritic organization and treadmilling of actin filament array in lamellipodia

J. Cell Biol.

(1999)

S.M. Hayden

Analysis of the interactions of actin depolymerizing factor with G- and F-actin

Biochemistry

(1993)

M. Hawkins

Human actin depolymerizing factor mediates a pH-sensitive destruction of actin filaments

Biochemistry

(1993)

M.F. Carlier

Actin depolymerizing factor (ADF/cofilin) enhances the rate of filament turnover: implication in actin-based motility

J. Cell Biol.

(1997)

A. McGough

Cofilin changes the twist of F-actin: implications for actin filament dynamics and cellular function

J. Cell Biol.

(1997)

V.E. Galkin

Actin depolymerizing factor stabilizes an existing state of F-actin and can change the tilt of F-actin subunits

J. Cell Biol.

(2001)

E. Nishida

Opposite effects of cofilin and profilin from porcine brain on rate of exchange of actin-bound adenosine 5(-triphosphate

Biochemistry

(1985)

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Trends in Cell Biology

ReviewADF/cofilin and actin dynamics in disease

Abstract

Section snippets

Overview of ADF/cofilin activity

Regulation of ADF/cofilins

Multiple actin-filament systems in cells

Actin turnover and ATP use

Diseases associated with ADF/cofilin and actin

ADF/cofilin and synaptic activity

Role of ADF/cofilins in muscle development

Endothelial-cell barrier function

Cancer

Infertility

Chemotaxis and activation of T cells and neutrophils

Concluding remarks

Acknowledgements

Am. J. Hum. Genet.

FEBS Lett.

Trends Cell Biol.

J. Mol. Biol.

Cell

J. Biol. Chem.

J. Mol. Biol.

Genomics

J. Biol. Chem.

Biochem. Biophys. Res. Commun.

Curr. Biol.

Cell

J. Biol. Chem.

Cell

Trends Neurosci.

Neuron

J. Biol. Chem.

J. Biol. Chem.

Trends Biochem. Sci.

Curr. Biol.

J. Biol. Chem.

Dev. Biol.

Dev. Biol.

A mutation in actin associated with neoplastic transformation

Fed. Proc.

The ADF homology (ADF-H) domain: a highly exploited actin-binding module

Mol. Biol. Cell

Proteins of the ADF/cofilin family: essential regulators of actin dynamics

Annu. Rev. Cell Dev. Biol.

The three mouse ADF/cofilins evolved to fulfill cell-specific requirements for actin dynamics

Mol. Biol. Cell

Cofilin is an essential component of the yeast cortical cytoskeleton

J. Cell Biol.

Isolation of a yeast essential gene, COF1, that encodes a homologue of mammalian cofilin, a low-Mr actin-binding and depolymerizing protein

Gene

Cofilin promotes rapid actin filament turnover in vivo

Nature

Arp2/3 complex and actin depolymerizing factor/cofilin in dendritic organization and treadmilling of actin filament array in lamellipodia

J. Cell Biol.

Analysis of the interactions of actin depolymerizing factor with G- and F-actin

Biochemistry

Human actin depolymerizing factor mediates a pH-sensitive destruction of actin filaments

Biochemistry

Actin depolymerizing factor (ADF/cofilin) enhances the rate of filament turnover: implication in actin-based motility

J. Cell Biol.

Cofilin changes the twist of F-actin: implications for actin filament dynamics and cellular function

J. Cell Biol.

Actin depolymerizing factor stabilizes an existing state of F-actin and can change the tilt of F-actin subunits

J. Cell Biol.

Opposite effects of cofilin and profilin from porcine brain on rate of exchange of actin-bound adenosine 5(-triphosphate

Biochemistry

Review
ADF/cofilin and actin dynamics in disease

Isolation of a yeast essential gene, COF1, that encodes a homologue of mammalian cofilin, a low-M_r actin-binding and depolymerizing protein