Control of Actin Reorganization by Slingshot, a Family of Phosphatases that Dephosphorylate ADF/Cofilin

Niwa, Ryusuke; Nagata-Ohashi, Kyoko; Takeichi, Masatoshi; Mizuno, Kensaku; Uemura, Tadashi

doi:10.1016/s0092-8674(01)00638-9

Cited by 619 publications

(647 citation statements)

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“…Cofilin is then regulated by four independent processes. First, the phosphorylation of cofilin on serine 3 by LIM kinase 1 (LIMK1) and its related kinases (LIMK2, the skeletal muscle-specific kinases Nik related kinase (NRK, also known as NESK) and testicular protein kinase 1 (TESK1) and TESK2) regulates cofilin by inhibiting its actin-binding activity [19][20][21][22] ; second, the dephosphorylation of serine 3 of cofilin by phosphatase types 1, 2A and 2B, slingshot (SSH) and chronophin phosphatases results in the activation of actin binding by cofilin [23][24][25][26] . Third, actin binding by cofilin is inhibited by binding to phosphatidylinositol-4,5-bisphosphate (PIP2) 27,28 , and cofilin activity is dependent on phospho lipase Cγ (PLCγ)-mediated hydrolysis of PIP2 (REFS 29,30); and fourth, changes in pH over the physiological range (6.8-7.4) as mediated by the Na-H exchanger protein can activate the severing activity of cofilin when it is in the dephosphorylated state [31][32][33][34] …”

Section: Nih Public Accessmentioning

confidence: 99%

“…Wing hair and bristle morphogenesis depend on the polymerization and bundling of actin filaments. Not surprisingly, transposon mutagenesis of the slingshot allele reduced the pool of activated cofilin, resulting in the increased accumulation of F-actin and the disruption of proper wing hair and bristle development 23 . In the nervous system, deletion of LIMK by transposon mutagenesis leads to aberrant development at the neuromuscular junction.…”

Section: Box 2 Linking Cofilin To Drosophila Melanogaster Morphogenesismentioning

confidence: 99%

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The cofilin pathway in breast cancer invasion and metastasis

Wang¹,

2007

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Recent evidence indicates that metastatic capacity is an inherent feature of breast tumours and not a rare, late acquired event. This has led to new models of metastasis. The interpretation of expression-profiling data in the context of these new models has identified the cofilin pathway as a major determinant of metastasis. Recent studies indicate that the overall activity of the cofilin pathway, and not that of any single gene within the pathway, determines the invasive and metastatic phenotype of tumour cells. These results predict that inhibitors directed at the output of the cofilin pathway will have therapeutic benefit in combating metastasis.Tumour cell motility is the hallmark of invasion and an essential step in metastasis 1,2 . The identification of molecular pathways that contribute to tumour cell motility and invasion is essential for understanding how motility is initiated in tumour cells and how the tumour microenvironment contributes to cell migration. The identification of the molecular pathways of tumour cell invasion will provide new diagnostic approaches and targets for the treatment of metastatic cancer. Recent studies using new technologies, including highdensity microarray-based expression profiling, intravital imaging and the collection of invasive tumour cells from live tumours, have started to extend the traditional model of metastasis and supply new diagnostic and therapeutic markers of metastatic disease.According to the traditional model of metastasis, metastases result from a process similar to Darwinian evolution whereby natural selection works on individual tumour cells to select © 2007 Nature Publishing Group Correspondence to: J.C. Condeeli@aecom.yu.edu. Competing interests statementThe authors declare no competing financial interests. for stable genetic changes. The cells so selected are very rare, and the metastatic cells that arise from this progressive selection of stable genetic mutations within the primary tumour cause metastasis late in tumour progression 3 . However, studies of mammary tumours in mice [4][5][6][7] , expression profiling of both whole human breast tumours 8,9 and the invasive subpopulation of tumour cells isolated from rat and mouse mammary tumours [10][11][12] suggest that the metastatic ability of breast tumours is encoded throughout the bulk of the primary tumour, involves transient changes in gene expression and is acquired at much earlier stages of tumour progression than postulated by the traditional model. These results suggest that a Darwinian-like evolution is accompanied by, and may contribute to, microenvironmentinduced transient changes in gene expression that support the invasive and metastatic phenotype. These results have led to new models where the microenvironment initiates the expression of genes that induce cell motility, invasion and metastasis 11,13 . In the 'tumour microenvironment invasion model' it is proposed that oncogenic mutations in tumour cells lead to microenvironments that are potentially encoded throughout the b...

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Section: Nih Public Accessmentioning

confidence: 99%

Section: Box 2 Linking Cofilin To Drosophila Melanogaster Morphogenesismentioning

confidence: 99%

The cofilin pathway in breast cancer invasion and metastasis

Wang¹,

2007

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“…Rock and Rho-kinase activate LIM-kinases, which are responsible for the phosphorylation and inactivation of actin depolymerization factors such as cofilin (Buchan et al 2002;Maekawa et al 1999;Sumi et al 1999). In contrast to the mechanisms of cofilin inactivation by LIMkinases, Slingshot was found to dephosphorylate phospho-cofilin and reactivate cofilin to depolymerize F-actin (Niwa et al 2002). We examined the levels of phospho-cofilin in B16 2F2 cells stimulated with compound 1.…”

Section: Dendrite Formationmentioning

confidence: 99%

Differentiation-inducing activity of lupane triterpenes on a mouse melanoma cell line

et al. 2006

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Lupane triterpenes were found to promote melanogenesis, a hallmark of B16 2F2 mouse melanoma cell differentiation. Studies of the structureactivity relationships demonstrated that the keto function at C-3 of the lupane skeleton played important roles in the melanogenic activities of lupane triterpenes on melanoma cells. The carbonyl group at C-17 of lupane triterpenes was essential against their apoptosis-inducing activity against human cancer cells via the inhibition of topoisomerase I. We investigated whether signaling mechanisms were involved in the stimulative effects of lupane triterpenes on the melanogenesis of B16 2F2 cells. In experiments using selective inhibitors against various signal transduction molecules and Western blotting analysis, it was suggested that p38 MAPK was involved in melanoma cell differentiation as a downstream effector of PKA. Lupeol (compound 1), a lupane triterpene, induced dendrite formations, a morphological hallmark of B16 2F2 cell differentiation by rearrangement of the actin cytoskeleton.The activation of cofilin, an actin depolymerizing factor, by compound 1 caused actin fiber disassembly in B16 2F2 cells. Furthermore, compound 1 was shown to inhibit the cell motilities of human melanoma and neuroblastoma in vitro.

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“…Recently, an ADF/cofilin phosphatase called slingshot was identified (Niwa et al 2002). However, its regulation is unknown.…”

Section: Rho Gtpase Signaling To Adf/cofilin In the Growth Conementioning

confidence: 99%

Regulation of Growth Cone Actin Dynamics by ADF/Cofilin

Gungabissoon

Bamburg

2003

J Histochem Cytochem.

126

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S U M M A R YNervous system development is reliant on neuronal pathfinding, the process in which axons are guided to their target cells by specific extracellular cues. The ability of neurons to extend over long distances in response to environmental guidance signals is made possible by the growth cone, a highly motile structure found at the end of neuronal processes. Growth cones detect directional cues and respond with either attractive or repulsive movements. The motility of growth cones is dependent on rapid reorganization of the actin cytoskeleton, presumably mediated by actin-associated proteins under the control of incoming guidance signals. This article reviews how one such family of proteins, the ADF/cofilins, are emerging as key regulators of growth cone actin dynamics. These proteins are essential for rapid actin turnover in a variety of different cell types. ADF/cofilins are heavily co-localized with actin in growth cones and are necessary for neurite outgrowth. ADF/cofilin activities are regulated through reversible phosphorylation by LIM kinases and slingshot phosphatases. LIM kinases are downstream effectors of the Rho GTPases Rho, Rac, and Cdc42. Growing evidence suggests that extracellular guidance cues may locally alter actin dynamics by regulating the activity of LIM kinase and ADF/cofilin phosphatases via the Rho GTPases. In this way, ADF/cofilins and their upstream effectors may be pivotal to our understanding of how guidance information is translated into physical alterations of the growth cone actin cytoskeleton.

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Control of Actin Reorganization by Slingshot, a Family of Phosphatases that Dephosphorylate ADF/Cofilin

Cited by 619 publications

References 70 publications

The cofilin pathway in breast cancer invasion and metastasis

The cofilin pathway in breast cancer invasion and metastasis

Differentiation-inducing activity of lupane triterpenes on a mouse melanoma cell line

Regulation of Growth Cone Actin Dynamics by ADF/Cofilin

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