Cables Links Cdk5 and c-Abl and Facilitates Cdk5 Tyrosine Phosphorylation, Kinase Upregulation, and Neurite Outgrowth

Zukerberg, Lawrence; Patrick, Gentry N.; Nikolic, Margareta; Humbert, Sandrine; Wu, Chin Lee; Lanier, Lorene M.; Gertler, Frank B.; Vidal, Marc; Etten, Richard A. Van; Tsai, Li Huei

doi:10.1016/s0896-6273(00)81200-3

Cited by 364 publications

(371 citation statements)

References 48 publications

Supporting

Mentioning

350

Contrasting

Order By: Relevance

“…20,4 CDK5 is known to contribute to the regulation of the actin and tubulin cytoskeleton, as well as regulation of membrane turnover and morphology, for example cell migration or endocytosis. [8][9][10] Altogether, this led us to hypothesize that CDK5, which is an upstream instigator of neuronal demise in various neuronal cell death models, might participate in a signal transduction pathway that links proapoptotic signals to the dynamic changes of mitochondrial morphology we had observed.…”

Section: Resultsmentioning

confidence: 88%

“…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%

“…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.…”

mentioning

confidence: 99%

See 2 more Smart Citations

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

et al. 2007

View full text Add to dashboard Cite

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...

show abstract

Section: Resultsmentioning

confidence: 88%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

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

et al. 2007

View full text Add to dashboard Cite

show abstract

“…Considering the higher abundance of Abl as compared to Arg during brain development (Moresco 2000) and that Abl is the only kinase that can be related to the phosphorylation of the S6K‐Ser 411 (Zukerberg et al. 2000; Markova et al. 2010), we propose Abl as the most probable candidate for the interaction with WIP between the Abl family members.…”

Section: Discussionmentioning

confidence: 99%

“…Several studies support a link between Abl and S6K: Cdk5 reaches maximum activation in response to Abl‐mediated phosphorylation (Zukerberg et al. 2000) and then, the Cdk5‐p35 kinase complex phosphorylates S6K at Ser 411 , allowing mTORC1‐mediated S6K activation in the nervous system (Hou et al. 2007).…”

Section: Discussionmentioning

confidence: 99%

Neuritic complexity of hippocampal neurons depends on WIP‐mediated mTORC1 and Abl family kinases activities

Franco-Villanueva

Antón

2015

Brain and Behavior

View full text Add to dashboard Cite

IntroductionNeuronal morphogenesis is governed mainly by two interconnected processes, cytoskeletal reorganization, and signal transduction. The actin‐binding molecule WIP (Wiskott‐Aldrich syndrome protein [WASP]‐interacting protein) was identified as a negative regulator of neuritogenesis. Although WIP controls activity of the actin‐nucleation‐promoting factor neural WASP (N‐WASP) during neuritic differentiation, its implication in signal transduction remains unknown.MethodsUsing primary neurons from WIP‐deficient and wild‐type mice we did an immunofluorescence, morphometric, and biochemical analysis of the signaling modified by WIP deficiency.ResultsHere, we describe the WIP contribution to the regulation of neuritic elaboration and ramification through modification in phosphorylation levels of several kinases that participate in the mammalian target of rapamycin complex 1 (mTORC1)‐p70S6K (phosphoprotein 70 ribosomal protein S6 kinase, S6K) intracellular signaling pathway. WIP deficiency induces an increase in the number of neuritic bifurcations and filopodial protrusions in primary embryonic neurons. This phenotype is not due to modifications in the activity of the phosphoinositide 3 kinase (PI3K)‐Akt pathway, but to reduced phosphorylation of the S6K residues Ser411 and Thr389. The resulting decrease in kinase activity leads to reduced S6 phosphorylation in the absence of WIP. Incubation of control neurons with pharmacological inhibitors of mTORC1 or Abl, two S6K regulators, conferred a morphology resembling that of WIP‐deficient neurons. Moreover, the preferential co‐distribution of phospho‐S6K with polymerized actin is altered in WIP‐deficient neurons.ConclusionThese experiments identify WIP as a member of a signaling cascade comprised of Abl family kinases, mTORC1 and S6K, which regulates neuron development and specifically, neuritic branching and complexity. Thus, we postulated a new role for WIP protein.

show abstract

Cell Cycle Control

Matthews¹,

Gerritsen²

2010

Targeting Protein Kinases for Cancer Therapy

View full text Add to dashboard Cite

Cables Links Cdk5 and c-Abl and Facilitates Cdk5 Tyrosine Phosphorylation, Kinase Upregulation, and Neurite Outgrowth

Cited by 364 publications

References 48 publications

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

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

Neuritic complexity of hippocampal neurons depends on WIP‐mediated mTORC1 and Abl family kinases activities

Cell Cycle Control

Contact Info

Product

Resources

About