Home LiteratureArticle Details
PMID: 12684437 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Control of growth cone motility and morphology by LIM kinase and Slingshot via phosphorylation and dephosphorylation of cofilin.

The Journal of neuroscience : the official journal of the Society for Neuroscience ·Vol. 23 ·No. 7 ·2003-04-01 ·Pages 2527-37

Endo M, Ohashi K, Sasaki Y, Goshima Y, Niwa R, Uemura T, Mizuno K

Abstract

Growth cone motility and morphology are based on actin-filament dynamics. Cofilin plays an essential role for the rapid turnover of actin filaments by severing and depolymerizing them. The activity of cofilin is repressed by phosphorylation at Ser3 by LIM kinase (LIMK, in which LIM is an acronym of the three gene products Lin-11, Isl-1, and Mec-3) and is reactivated by dephosphorylation by phosphatases, termed Slingshot (SSH). We investigated the roles of cofilin, LIMK, and SSH in the growth cone motility and morphology and neurite extension by expressing fluorescence protein-labeled cofilin, LIMK1, SSH1, or their mutants in chick dorsal root ganglion (DRG) neurons and then monitoring live images of growth cones by time-lapse video fluorescence microscopy. The expression of LIMK1 remarkably repressed growth cone motility and neurite extension, whereas the expression of SSH1 or a nonphosphorylatable S3A mutant of cofilin enhanced these events. The fan-like shape of growth cones was disorganized by the expression of any of these proteins. The repressive effects on growth cone behavior by LIMK1 expression were significantly rescued by the coexpression of S3A-cofilin or SSH1. 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. Using various mutants of cofilin, we also obtained evidence that the actin-filament-severing activity of cofilin is critical for growth cone motility and neurite extension.

MeSH Terms
Actin Cytoskeleton/metabolism Actin Depolymerizing Factors Amino Acid Sequence Animals COS Cells Cells, Cultured Chick Embryo Cloning, Molecular Ganglia, Spinal/cytology,enzymology Growth Cones/enzymology,physiology,ultrastructure HeLa Cells Humans Lim Kinases Microfilament Proteins/metabolism Molecular Sequence Data Movement Neurons/enzymology Phosphoprotein Phosphatases/physiology Phosphorylation Protein Kinases/analysis,genetics,physiology
Chemicals
Actin Depolymerizing Factors Microfilament Proteins Protein Kinases LIMK1 protein, human Lim Kinases Phosphoprotein Phosphatases
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Endo Mitsuharu
Department of Biomolecular Sciences, Graduate School of Life Sciences, Tohoku University, Sendai 980-8578, Japan.
Ohashi Kazumasa
Sasaki Yukio
Goshima Yoshio
Niwa Ryusuke
Uemura Tadashi
Mizuno Kensaku
References (52)
52 references, click to expand
  1. Growth cone guidance: first steps towards a deeper understanding.
    Annu Rev Neurosci. 1999;22:351-88 PMID: 10202543
  2. Signaling from Rho to the actin cytoskeleton through protein kinases ROCK and LIM-kinase.
    Science. 1999 Aug 6;285(5429):895-8 PMID: 10436159
  3. Activation of LIM-kinase by Pak1 couples Rac/Cdc42 GTPase signalling to actin cytoskeletal dynamics.
    Nat Cell Biol. 1999 Sep;1(5):253-9 PMID: 10559936
  4. Control of actin dynamics in cell motility. Role of ADF/cofilin.
    J Biol Chem. 1999 Nov 26;274(48):33827-30 PMID: 10567336
  5. Two activities of cofilin, severing and accelerating directional depolymerization of actin filaments, are affected differentially by mutations around the actin-binding helix.
    EMBO J. 1999 Dec 1;18(23):6752-61 PMID: 10581248
  6. Proteins of the ADF/cofilin family: essential regulators of actin dynamics.
    Annu Rev Cell Dev Biol. 1999;15:185-230 PMID: 10611961
  7. Cofilin phosphorylation and actin cytoskeletal dynamics regulated by rho- and Cdc42-activated LIM-kinase 2.
    J Cell Biol. 1999 Dec 27;147(7):1519-32 PMID: 10613909
  8. Regulating actin-filament dynamics in vivo.
    Trends Biochem Sci. 2000 Jan;25(1):19-23 PMID: 10637608
  9. Rho-associated kinase ROCK activates LIM-kinase 1 by phosphorylation at threonine 508 within the activation loop.
    J Biol Chem. 2000 Feb 4;275(5):3577-82 PMID: 10652353
  10. Role of cofilin in epidermal growth factor-stimulated actin polymerization and lamellipod protrusion.
    J Cell Biol. 2000 Feb 7;148(3):531-42 PMID: 10662778
  11. Increase in neurite outgrowth mediated by overexpression of actin depolymerizing factor.
    J Neurosci. 2000 Apr 1;20(7):2459-69 PMID: 10729326
  12. Ephrin-A5 induces collapse of growth cones by activating Rho and Rho kinase.
    J Cell Biol. 2000 Apr 17;149(2):263-70 PMID: 10769020
  13. Regulation of the actin cycle in vivo by actin filament severing.
    Proc Natl Acad Sci U S A. 2000 Jun 6;97(12):6532-7 PMID: 10823888
  14. A critical role for a Rho-associated kinase, p160ROCK, in determining axon outgrowth in mammalian CNS neurons.
    Neuron. 2000 May;26(2):431-41 PMID: 10839361
  15. Regulating actin dynamics in neuronal growth cones by ADF/cofilin and rho family GTPases.
    J Neurobiol. 2000 Aug;44(2):126-44 PMID: 10934317
  16. Molecular mechanisms controlling actin filament dynamics in nonmuscle cells.
    Annu Rev Biophys Biomol Struct. 2000;29:545-76 PMID: 10940259
  17. Phosphorylation of ADF/cofilin abolishes EGF-induced actin nucleation at the leading edge and subsequent lamellipod extension.
    J Cell Biol. 2000 Nov 27;151(5):1119-28 PMID: 11086013
  18. LIM-kinase 2 induces formation of stress fibres, focal adhesions and membrane blebs, dependent on its activation by Rho-associated kinase-catalysed phosphorylation at threonine-505.
    Biochem J. 2001 Feb 15;354(Pt 1):149-59 PMID: 11171090
  19. Repulsive factors and axon regeneration in the CNS.
    Curr Opin Neurobiol. 2001 Feb;11(1):89-94 PMID: 11179877
  20. Rho GTPases in growth cone guidance.
    Curr Opin Neurobiol. 2001 Feb;11(1):103-10 PMID: 11179879
  21. The cell biology of neuronal navigation.
    Nat Cell Biol. 2001 Mar;3(3):E81-8 PMID: 11231595
  22. Rho GTPases in neuronal morphogenesis.
    Nat Rev Neurosci. 2000 Dec;1(3):173-80 PMID: 11257905
  23. Phosphorylation of cofilin by LIM-kinase is necessary for semaphorin 3A-induced growth cone collapse.
    Nat Neurosci. 2001 Apr;4(4):367-73 PMID: 11276226
  24. Cofilin phosphorylation by protein kinase testicular protein kinase 1 and its role in integrin-mediated actin reorganization and focal adhesion formation.
    Mol Biol Cell. 2001 Apr;12(4):1131-45 PMID: 11294912
  25. Signal-regulated ADF/cofilin activity and growth cone motility.
    Mol Neurobiol. 2000 Feb-Apr;21(1-2):97-107 PMID: 11327152
  26. How is actin polymerization nucleated in vivo?
    Trends Cell Biol. 2001 Jul;11(7):288-93 PMID: 11413039
  27. Cofilin phosphorylation and actin reorganization activities of testicular protein kinase 2 and its predominant expression in testicular Sertoli cells.
    J Biol Chem. 2001 Aug 17;276(33):31449-58 PMID: 11418599
  28. Cell-type-specific expression of a TESK1 promoter-linked lacZ gene in transgenic mice.
    Biochem Biophys Res Commun. 2001 Aug 24;286(3):566-73 PMID: 11511097
  29. Control of actin reorganization by Slingshot, a family of phosphatases that dephosphorylate ADF/cofilin.
    Cell. 2002 Jan 25;108(2):233-46 PMID: 11832213
  30. Mitosis-specific activation of LIM motif-containing protein kinase and roles of cofilin phosphorylation and dephosphorylation in mitosis.
    J Biol Chem. 2002 Jun 14;277(24):22093-102 PMID: 11925442
  31. The actin-severing activity of cofilin is exerted by the interplay of three distinct sites on cofilin and essential for cell viability.
    Biochem J. 2002 Jul 1;365(Pt 1):147-55 PMID: 12113256
  32. Abnormal spine morphology and enhanced LTP in LIMK-1 knockout mice.
    Neuron. 2002 Jul 3;35(1):121-33 PMID: 12123613
  33. Fyn and Cdk5 mediate semaphorin-3A signaling, which is involved in regulation of dendrite orientation in cerebral cortex.
    Neuron. 2002 Aug 29;35(5):907-20 PMID: 12372285
  34. Cytoskeletal dynamics and nerve growth.
    Neuron. 1988 Nov;1(9):761-72 PMID: 3078414
  35. Distribution and cellular localization of actin depolymerizing factor.
    J Cell Biol. 1987 Dec;105(6 Pt 1):2817-25 PMID: 3320057
  36. Limk1 is predominantly expressed in neural tissues and phosphorylates serine, threonine and tyrosine residues in vitro.
    Oncogene. 1995 Oct 5;11(7):1271-81 PMID: 7478547
  37. Making the connection: cytoskeletal rearrangements during growth cone guidance.
    Cell. 1995 Oct 20;83(2):171-6 PMID: 7585934
  38. Reactivation of phosphorylated actin depolymerizing factor and identification of the regulatory site.
    J Biol Chem. 1995 Jul 21;270(29):17582-7 PMID: 7615564
  39. Collapsin-induced growth cone collapse mediated by an intracellular protein related to UNC-33.
    Nature. 1995 Aug 10;376(6540):509-14 PMID: 7637782
  40. LIMK-1 and LIMK-2, two members of a LIM motif-containing protein kinase family.
    Oncogene. 1995 Aug 17;11(4):701-10 PMID: 7651734
  41. Molecular cloning of a chicken lung cDNA encoding a novel protein kinase with N-terminal two LIM/double zinc finger motifs.
    J Biochem. 1994 Sep;116(3):636-42 PMID: 7852284
  42. Identification of a human cDNA encoding a novel protein kinase with two repeats of the LIM/double zinc finger motif.
    Oncogene. 1994 Jun;9(6):1605-12 PMID: 8183554
  43. Identification and characterization of a novel family of serine/threonine kinases containing two N-terminal LIM motifs.
    J Biol Chem. 1995 Dec 29;270(52):31321-30 PMID: 8537403
  44. The ADF/cofilin proteins: stimulus-responsive modulators of actin dynamics.
    Mol Biol Cell. 1995 Nov;6(11):1423-31 PMID: 8589446
  45. LIM-kinase1 hemizygosity implicated in impaired visuospatial constructive cognition.
    Cell. 1996 Jul 12;86(1):59-69 PMID: 8689688
  46. The molecular biology of axon guidance.
    Science. 1996 Nov 15;274(5290):1123-33 PMID: 8895455
  47. Actin depolymerizing factor (ADF/cofilin) enhances the rate of filament turnover: implication in actin-based motility.
    J Cell Biol. 1997 Mar 24;136(6):1307-22 PMID: 9087445
  48. Comparison of tissue distribution of two novel serine/threonine kinase genes containing the LIM motif (LIMK-1 and LIMK-2) in the developing rat.
    Brain Res Mol Brain Res. 1997 May;45(2):247-54 PMID: 9149099
  49. Rac1 mediates collapsin-1-induced growth cone collapse.
    J Neurosci. 1997 Aug 15;17(16):6256-63 PMID: 9236236
  50. Rho GTPases and the actin cytoskeleton.
    Science. 1998 Jan 23;279(5350):509-14 PMID: 9438836
  51. Regulation of actin dynamics through phosphorylation of cofilin by LIM-kinase.
    Nature. 1998 Jun 25;393(6687):805-9 PMID: 9655397
  52. Cofilin phosphorylation by LIM-kinase 1 and its role in Rac-mediated actin reorganization.
    Nature. 1998 Jun 25;393(6687):809-12 PMID: 9655398
Article Info
Journal
The Journal of neuroscience : the official journal of the Society for Neuroscience
Abbr.
J Neurosci
ISSN
1529-2401
Published
2003-04-01
Pages
2527-37
Language
English
Region
United States
NLM ID
8102140
PMCID
PMC6742113
Subset
IM
External Links
PubMed source PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: [email protected]

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2