Phosphorylation of Pak1 by the p35/Cdk5 Kinase Affects Neuronal Morphology

Rashid, T.; Banerjee, Monisha; Nikolic, Margareta

doi:10.1074/jbc.m105599200

Cited by 136 publications

(117 citation statements)

References 61 publications

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“…This also reveals that between Rac1 and its effector Pak1, several molecules, including transcriptional factors such as NFATc1 and kinases such as CDK6/4, are recruited in the phosphorylation and activation of Pak1 by its modulator Rac1. In support of a role of CDKs in the phosphorylation and activation of Pak1, previous studies have also shown that CDK5, a neuronal specific CDK, mediates Pak1 phosphorylation and activation during neurite outgrowth (50). Besides, this study reveals for the first time that NFATc1, via its involvement in the mediation of Pak1 activation, plays a role in F-actin cytoskeletal remodeling.…”

Section: Discussionsupporting

confidence: 78%

Nuclear Factor of Activated T Cells c1 Mediates p21-activated Kinase 1 Activation in the Modulation of Chemokine-induced Human Aortic Smooth Muscle Cell F-actin Stress Fiber Formation, Migration, and Proliferation and Injury-induced Vascular Wall Remodeling

Kundumani‐Sridharan

Singh

Kumar

et al. 2013

Journal of Biological Chemistry

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Background: We explore the mechanisms by which NFATc1 mediates vascular wall remodeling. Results: MCP1 activates Pak1 in a Rac1-NFATc1-cyclin D1-CDK6-CDK4-dependent manner in the mediation of HASMC migration and proliferation. Conclusion: Downstream of Rac1, NFATc1, via the cyclin D1-CDK6-CDK4 signaling axis, mediates Pak1 activation in the modulation of vascular wall remodeling. Significance: Interference with NFATc1 activation could represent a novel therapeutic approach for the treatment of restenosis.

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Section: Discussionsupporting

confidence: 78%

Nuclear Factor of Activated T Cells c1 Mediates p21-activated Kinase 1 Activation in the Modulation of Chemokine-induced Human Aortic Smooth Muscle Cell F-actin Stress Fiber Formation, Migration, and Proliferation and Injury-induced Vascular Wall Remodeling

Kundumani‐Sridharan

Singh

Kumar

et al. 2013

Journal of Biological Chemistry

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“…CDK5 is an apical instigator in many neuronal cell death cascades 15,14,27,17 and phosphorylates various proteins implicated in cytoskeletal organization. 28,29 In addition, CDK5 has previously been shown to be implicated in various cellular events involving turnover of biological membranes, for example cell migration, axonal outgrowth or endocytosis. 10,27,11 These cellular functions also require cytoskelettal structures, and we considered that, albeit a simplifying view, the process of mitochondrial fission shares mechanistic similarities with the cleavage of cell membranes during 'pinching off' of endocytotic vesicles.…”

Section: Discussionmentioning

confidence: 99%

Cyclin-dependent kinase 5 is an upstream regulator of mitochondrial fission during neuronal apoptosis

et al. 2007

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Under physiological conditions, mitochondrial morphology dynamically shifts between a punctuate appearance and tubular networks. However, little is known about upstream signal transduction pathways that regulate mitochondrial morphology. We show that mitochondrial fission is a very early and kinetically invariant event during neuronal cell death, which causally contributes to cytochrome c release and neuronal apoptosis. Using a small molecule CDK5 inhibitor, as well as a dominantnegative CDK5 mutant and RNAi knockdown experiments, we identified CDK5 as an upstream signalling kinase that regulates mitochondrial fission during apoptosis of neurons. Vice versa, our study shows that mitochondrial fission is a modulator contributing to CDK5-mediated neurotoxicity. Thereby, we provide a link that allows integration of CDK5 into established neuronal apoptosis pathways. Mitochondria can acquire a broad range of morphologies, from a punctuate shape to a tubular appearance or even extended networks. Several proteins, most of them belonging to the family of large GTPases, have been identified that energy-dependently regulate mitochondrial morphology and subcellular distribution by promoting either fission (Fis1, dynamin-related protein 1 (Drp1), MTP18) or fusion of mitochondria (Mfn1/2 and Opa1). 1-3 As a potential upstream regulatory factor, the actin cytoskeleton has been shown to be a prerequisite for mitochondrial fission, possibly by its influence on Drp1 recruitment to mitochondria. 4 Apoptotic release of the mitochondrial cytochrome c and other proapoptotic mitochondrial proteins results in formation of the so-called apoptosome, which in turn activates downstream effector caspases with death executing function. 5 This intrinsic, mitochondrial death pathway is relevant for most forms of neuronal apoptosis, in contrast to extrinsic, for example death receptor mediated, activation of programmed cell death. 6 However, despite the contribution of mitochondrial dysfunction specifically to the demise of neurons, there is only scarce knowledge about mitochondrial fission during neuronal apoptosis, nor about its functional contribution to neuronal cell death. Furthermore, little is known about upstream regulatory pathways for mitochondrial morphology in general.Cyclin-dependent kinase 5 (CDK5) is a member of the CDK family, but, distinct from other CDKs, it does not participate in cell cycle regulation. 7 Instead, CDK5 is physiologically implicated in cytoskeletal functions, as well as regulation of membrane turnover and morphology, for example cell migration or endocytosis. Moreover, it is involved in neuronspecific functions including, for example, synaptic plasticity, axonal outgrowth or transmitter release. [8][9][10][11] In neurological diseases, deregulated CDK5 turned out to be an apical instigator of neuronal cell death cascades. Amyloid-toxicity was shown to induce calpain-mediated cleavage of the CDK5 activators p35 or p39 to p25 and p29. This leads to redistribution and overactivation of CDK5 after its association...

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“…Recombinant GST-Nb1 1-144 and GST-Nb1A95 1-144 proteins were produced and subjected to radioactive kinase assay as described previously (Rashid et al, 2001). …”

Section: Kinase Assaysmentioning

confidence: 99%

Neurabin-I Is Phosphorylated by Cdk5: Implications for Neuronal Morphogenesis and Cortical Migration

Causeret

Jacobs

Terao

et al. 2007

MBoC

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The correct morphology and migration of neurons, which is essential for the normal development of the nervous system, is enabled by the regulation of their cytoskeletal elements. We reveal that Neurabin-I, a neuronal-specific F-actin-binding protein, has an essential function in the developing forebrain. We show that gain and loss of Neurabin-I expression affect neuronal morphology, neurite outgrowth, and radial migration of differentiating cortical and hippocampal neurons, suggesting that tight regulation of Neurabin-I function is required for normal forebrain development. Importantly, loss of Neurabin-I prevents pyramidal neurons from migrating into the cerebral cortex, indicating its essential role during early stages of corticogenesis. We demonstrate that in neurons Rac1 activation is affected by the expression levels of Neurabin-I. Furthermore, the Cdk5 kinase, a key regulator of neuronal migration and morphology, directly phosphorylates Neurabin-I and controls its association with F-actin. Mutation of the Cdk5 phosphorylation site reduces the phenotypic consequences of Neurabin-I overexpression both in vitro and in vivo, suggesting that Neurabin-I function depends, at least in part, on its phosphorylation status. Together our findings provide new insight into the signaling pathways responsible for controlled changes of the F-actin cytoskeleton that are required for normal development of the forebrain.

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Phosphorylation of Pak1 by the p35/Cdk5 Kinase Affects Neuronal Morphology

Cited by 136 publications

References 61 publications

Nuclear Factor of Activated T Cells c1 Mediates p21-activated Kinase 1 Activation in the Modulation of Chemokine-induced Human Aortic Smooth Muscle Cell F-actin Stress Fiber Formation, Migration, and Proliferation and Injury-induced Vascular Wall Remodeling

Nuclear Factor of Activated T Cells c1 Mediates p21-activated Kinase 1 Activation in the Modulation of Chemokine-induced Human Aortic Smooth Muscle Cell F-actin Stress Fiber Formation, Migration, and Proliferation and Injury-induced Vascular Wall Remodeling

Cyclin-dependent kinase 5 is an upstream regulator of mitochondrial fission during neuronal apoptosis

Neurabin-I Is Phosphorylated by Cdk5: Implications for Neuronal Morphogenesis and Cortical Migration

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