Pak3 inhibits local actin filament formation to regulate global cell polarity

Asano, Yukako; Jiménez-Dalmaroni, Andrea; Liverpool, Tanniemola B.; Marchetti, M. C.; Giomi, Luca; Kiger, Amy A.; Duke, Thomas; Baum, Buzz

doi:10.2976/1.3100548

Cited by 29 publications

(39 citation statements)

References 38 publications

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“…Our results suggest that the increase in filopodia induced by pak3 overexpression in cell culture (Asano et al 2009) also occurs in vivo, providing further support for Pak3-mediated regulation of the actin cytoskeleton. In cultured mammalian cells, Rac or Cdc42 activation not only leads to changes in actin polymerization, but also induces phosphorylation of Stathmin by Pak1, inactivating Stathmin's microtubuledestabilizing activity (Daub et al 2001).…”

Section: Discussionmentioning

confidence: 52%

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Loss of Drosophila melanogaster p21-activated kinase 3 Suppresses Defects in Synapse Structure and Function Caused by spastin Mutations

et al. 2011

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Microtubules are dynamic structures that must elongate, disassemble, and be cleaved into smaller pieces for proper neuronal development and function. The AAA ATPase Spastin severs microtubules along their lengths and is thought to regulate the balance between long, stable filaments and shorter fragments that seed extension or are transported. In both Drosophila and humans, loss of Spastin function results in reduction of synaptic connections and disabling motor defects. To gain insight into how spastin is regulated, we screened the Drosophila melanogaster genome for deletions that modify a spastin overexpression phenotype, eye size reduction. One suppressor region deleted p21-activated kinase 3 (pak3), which encodes a member of the Pak family of actin-regulatory enzymes, but whose in vivo function is unknown. We show that pak3 mutants have only mild synaptic defects at the larval neuromuscular junction, but exhibit a potent genetic interaction with spastin mutations. Aberrant bouton morphology, microtubule distribution, and synaptic transmission caused by spastin loss of function are all restored to wild type when pak3 is simultaneously reduced. Neuronal overexpression of pak3 induces actin-rich thin projections, suggesting that it functions in vivo to promote filopodia during presynaptic terminal arborization. pak3 therefore regulates synapse development in vivo, and when mutated, suppresses the synaptic defects that result from spastin loss.

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Section: Discussionmentioning

confidence: 52%

“…In contrast to these diverse functions of dPak and mbt, pak3 remains uncharacterized in vivo. In cultured Drosophila S2 cells, pak3 overexpression induces extensive filopodial formation, while reduction results in a polarized lamellipodial distribution of actin filaments and induction of migration (Asano et al 2009). …”

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confidence: 99%

Loss of Drosophila melanogaster p21-activated kinase 3 Suppresses Defects in Synapse Structure and Function Caused by spastin Mutations

et al. 2011

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“…It should be emphasized that 2D geometry is essential for understanding dynamics of the observed pattern and their transitions. In earlier models based on one-dimensional geometry (6,15,30,36), a switch of patterns such as reversion of wave propagation along the cell periphery occurs merely by stochastic noise (6). The current study suggests that such a view of pattern transition in many cases could be an oversimplification, because topological charge of the spiral core is robust and cannot simply be flipped by random noise.…”

Section: Phase-map Analysis Reveals Birth and Death Of Spatial Phasementioning

confidence: 80%

“…Future studies that include mutant analysis should allow comparison of details that delineate the existing models. Also of theoretical interest is to relate similar waves of PIP3 and/or F-actin observed in animal cells (7,(36)(37)(38) and other amoeba species (28). Although other feedback mechanisms in For weak feedback strength, waves were extinguished at the boundary so that they propagated only transiently as observed in LY294002-treated cells (Fig.…”

Section: Phase-map Analysis Reveals Birth and Death Of Spatial Phasementioning

confidence: 99%

Phase geometries of two-dimensional excitable waves govern self-organized morphodynamics of amoeboid cells

Taniguchi¹,

Ishihara

Oonuki³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

137

182

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In both randomly moving Dictyostelium and mammalian cells, phosphatidylinositol (3,4,5)-trisphosphate and F-actin are known to propagate as waves at the membrane and act to push out the protruding edge. To date, however, the relationship between the wave geometry and the patterns of amoeboid shape change remains elusive. Here, by using phase map analysis, we show that morphology dynamics of randomly moving Dictyostelium discoideum cells can be characterized by the number, topology, and position of spatial phase singularities, i.e., points that represent organizing centers of rotating waves. A single isolated singularity near the cellular edge induced a rotational protrusion, whereas a pair of singularities supported a symmetric extension. These singularities appeared by strong phase resetting due to de novo nucleation at the back of preexisting waves. Analysis of a theoretical model indicated excitability of the system that is governed by positive feedback from phosphatidylinositol (3,4,5)-trisphosphate to PI3-kinase activation, and we showed experimentally that this requires F-actin. Furthermore, by incorporating membrane deformation into the model, we demonstrated that geometries of competing waves explain most of the observed semiperiodic changes in amoeboid morphology.reaction-diffusion | oscillations | excitable media | self-organization | PTEN

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“…p21-activated kinases (Paks) have been shown to regulate polarity both in single and multicellular systems (Asano et al, 2009;Conder et al, 2007). The Drosophila genome encodes three Paks: Pak, Pak3 and Mushroom bodies tiny (Mbt; also known as Drosophila Pak2).…”

Section: Introductionmentioning

confidence: 99%

dPak3 regulates apical-basal polarity in migrating border cells during Drosophila oogenesis

et al. 2015

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Group cell migration is a highly coordinated process that is involved in a number of physiological events such as morphogenesis, wound healing and tumor metastasis. Unlike single cells, collectively moving cells are physically attached to each other and retain some degree of apical-basal polarity during the migratory phase. Although much is known about direction sensing, how polarity is regulated in multicellular movement remains unclear. Here we report the role of the protein kinase Pak3 in maintaining apical-basal polarity in migrating border cell clusters during Drosophila oogenesis. Pak3 is enriched in border cells and downregulation of its function impedes border cell movement. Time-lapse imaging suggests that Pak3 affects protrusive behavior of the border cell cluster, specifically regulating the stability and directionality of protrusions. Pak3 functions downstream of guidance receptor signaling to regulate the level and distribution of F-actin in migrating border cells. We also provide evidence that Pak3 genetically interacts with the lateral polarity marker Scribble and that it regulates JNK signaling in the moving border cells. Since Pak3 depletion results in mislocalization of several apical-basal polarity markers and overexpression of Jra rescues the polarity of the Pak3-depleted cluster, we propose that Pak3 functions through JNK signaling to modulate apical-basal polarity of the migrating border cell cluster. We also observe loss of apical-basal polarity in Rac1-depleted border cell clusters, suggesting that guidance receptor signaling functions through Rac GTPase and Pak3 to regulate the overall polarity of the cluster and mediate efficient collective movement of the border cells to the oocyte boundary.

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Pak3 inhibits local actin filament formation to regulate global cell polarity

Cited by 29 publications

References 38 publications

Loss of Drosophila melanogaster p21-activated kinase 3 Suppresses Defects in Synapse Structure and Function Caused by spastin Mutations

Loss of Drosophila melanogaster p21-activated kinase 3 Suppresses Defects in Synapse Structure and Function Caused by spastin Mutations

Phase geometries of two-dimensional excitable waves govern self-organized morphodynamics of amoeboid cells

dPak3 regulates apical-basal polarity in migrating border cells during Drosophila oogenesis

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