Localized Activation of p21-Activated Kinase Controls Neuronal Polarity and Morphology

Jacobs, Tom; Causeret, Frédéric; Nishimura, Yoshiaki; Terao, Mineko; Norman, Adele; Hoshino, Mikio; Nikolic, Margareta

doi:10.1523/jneurosci.0765-07.2007

Cited by 67 publications

(75 citation statements)

References 60 publications

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“…6 B, available at www.jneurosci.org as supplemental material). Expression of wild-type or active forms of PAK (Sells et al, 1997) was also unable to rescue the axon forming capacity of knock-out neurons (data not shown); the latter finding is consistent with recent reports showing that PAK hyperactivation disrupts neuronal polarity (Jacobs et al, 2007). Our favored interpretation of the above results is that a concentrated pool of active Cdc42 in the growth cone would be required to locally recruit or activate cofilin, as well as other effectors such as PAK or GSK-3, which can then promote axon growth.…”

Section: Cofilin Activity Promotes Axon Formationsupporting

confidence: 92%

“…3G, available at www.jneurosci.org as supplemental material). LIM kinase can be phosphorylated by PAK (Edwards et al, 1999), which is specifically activated in axons and affects the establishment of neuronal polarity (Jacobs et al, 2007). However, the activity of PAK in the knock-out was actually reduced, as could be expected in the absence of its upstream activator Cdc42, but inconsistent with the involvement of a PAK-dependent pathway in stimulating LIM kinase.…”

Section: Increased Cofilin Phosphorylation In the Absence Of Cdc42mentioning

confidence: 97%

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Cdc42 Regulates Cofilin during the Establishment of Neuronal Polarity

Garvalov¹,

Flynn²,

Neukirchen³

et al. 2007

J. Neurosci.

233

221

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The establishment of polarity is an essential process in early neuronal development. Although a number of molecules controlling neuronal polarity have been identified, genetic evidence about their physiological roles in this process is mostly lacking. We analyzed the consequences of loss of Cdc42, a central regulator of polarity in multiple systems, on the polarization of mammalian neurons. Genetic ablation of Cdc42 in the brain led to multiple abnormalities, including striking defects in the formation of axonal tracts. Neurons from the Cdc42 null animals sprouted neurites but had a strongly suppressed ability to form axons both in vivo and in culture. This was accompanied by disrupted cytoskeletal organization, enlargement of the growth cones, and inhibition of filopodial dynamics. Axon formation in the knock-out neurons was rescued by manipulation of the actin cytoskeleton, indicating that the effects of Cdc42 ablation are exerted through modulation of actin dynamics. In addition, the knock-outs showed a specific increase in the phosphorylation (inactivation) of the Cdc42 effector cofilin. Furthermore, the active, nonphosphorylated form of cofilin was enriched in the axonal growth cones of wild-type, but not of mutant, neurons. Importantly, cofilin knockdown resulted in polarity defects quantitatively analogous to the ones seen after Cdc42 ablation. We conclude that Cdc42 is a key regulator of axon specification, and that cofilin is a physiological downstream effector of Cdc42 in this process.

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Section: Cofilin Activity Promotes Axon Formationsupporting

confidence: 92%

Section: Increased Cofilin Phosphorylation In the Absence Of Cdc42mentioning

confidence: 97%

Cdc42 Regulates Cofilin during the Establishment of Neuronal Polarity

Garvalov¹,

Flynn²,

Neukirchen³

et al. 2007

J. Neurosci.

233

221

View full text Add to dashboard Cite

show abstract

“…Important actin-regulating factors in neuronal polarization and neurite outgrowth include cofilin, Nap-1, and the Ena/Vasp family of proteins (Dent et al, 2007;Garvalov et al, 2007;Jacobs et al, 2007;Yokota et al, 2007). Pharmacological studies depicted microtubule stability as a putative determining factor for neuronal polarization .…”

Section: Discussionmentioning

confidence: 99%

Cytoplasmic Linker Proteins Regulate Neuronal Polarization through Microtubule and Growth Cone Dynamics

Neukirchen¹,

Bradke²

2011

J. Neurosci.

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Axon formation is a hallmark of initial neuronal polarization. This process is thought to be regulated by enhanced microtubule stability in the subsequent axon and changes in actin dynamics in the future axonal growth cone. Here, we show that the microtubule end-binding proteins cytoplasmic linker protein (CLIP)-115 and CLIP-170 were enriched in the axonal growth cone and extended into the actin-rich domain of the growth cone. CLIPs were necessary for axon formation and sufficient to induce an axon. The regulation of axonal microtubule stabilization by CLIPs enabled the protrusion of microtubules into the leading edge of the axonal growth cone. Moreover, CLIPs positively regulated growth cone dynamics and restrained actin arc formation, which was necessary for axon growth. In fact, in neurons without CLIP activity, axon formation was restored by actin destabilization or myosin II inhibition. Together, our data suggest that CLIPs enable neuronal polarization by controlling the stabilization of microtubules and growth cone dynamics.

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“…APC siRNA (Segditsas et al, 2008), PAK1 shRNA (Jacobs et al, 2007) and b-catenin shRNA (van de Wetering et al, 2003) were used as described previously. All siRNAs were synthesized by GenePharma (Shanghai, China).…”

Section: Methodsmentioning

confidence: 99%

A Rac1/PAK1 cascade controls β-catenin activation in colon cancer cells

et al. 2011

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P21-activated kinase 1 (PAK1) is associated with colon cancer progression and metastasis, whereas the molecular mechanism remains elusive. Here, we show that downregulation of PAK1 in colon cancer cells reduces total b-catenin level, as well as cell proliferation. Mechanistically, PAK1 directly phosphorylates b-catenin proteins at Ser675 site and this leads to more stable and transcriptional active b-catenin. Corroborating these results, PAK1 is required for full Wnt signaling, and superactivation of b-catenin is achieved by simultaneous knockdown of adenomatous polyposis coli protein and activation of PAK1. Moreover, we show that Rac1 functions upstream of PAK1 in colon cancer cells and contributes to b-catenin phosphorylation and accumulation. We conclude that a Rac1/PAK1 cascade controls b-catenin S675 phosphorylation and full activation in colon cancer cells. Supporting this conclusion, overexpression of PAK1 is observed in 70% of colon cancer samples and is correlated with massive b-catenin accumulation.

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Localized Activation of p21-Activated Kinase Controls Neuronal Polarity and Morphology

Cited by 67 publications

References 60 publications

Cdc42 Regulates Cofilin during the Establishment of Neuronal Polarity

Cdc42 Regulates Cofilin during the Establishment of Neuronal Polarity

Cytoplasmic Linker Proteins Regulate Neuronal Polarization through Microtubule and Growth Cone Dynamics

A Rac1/PAK1 cascade controls β-catenin activation in colon cancer cells

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