Going out of the brain: Non-nervous system physiological and pathological functions of Cdk5

Contreras-Vallejos, Erick; Utreras, Elías; González-Billault, Christian

doi:10.1016/j.cellsig.2011.08.022

Cited by 82 publications

(86 citation statements)

References 126 publications

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“…This is because unlike other CDKs, CDK5 is activated by p35 and p39, two proteins that are expressed only in the brain (10,11). CDK5 also binds to D-type and E-type cyclins but does not display kinase activity (12). Therefore, Cdk5 is often regarded as a neuron-specific kinase, which is not involved in cell cycle control, but instead plays an essential role in neuronal development, including neuronal migration, axon guidance, and synaptic plasticity (13)(14)(15)(16).…”

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confidence: 99%

Proteomic Analysis of the Human Cyclin-dependent Kinase Family Reveals a Novel CDK5 Complex Involved in Cell Growth and Migration

Wang

et al. 2014

Molecular & Cellular Proteomics

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Cyclin-dependent kinases (CDKs) are the catalytic subunits of a family of mammalian heterodimeric serine/threonine kinases that play critical roles in the control of cell-cycle progression, transcription, and neuronal functions. However, the functions, substrates, and regulation of many CDKs are poorly understood. To systematically investigate these features of CDKs, we conducted a proteomic analysis of the CDK family and identified their associated protein complexes in two different cell lines using a modified SAINT (Significance Analysis of INTeractome) method. The mass spectrometry data were deposited to ProteomeXchange with identifier PXD000593 and DOI 10.6019/PXD000593. We identified 753 high-confidence candidate interaction proteins (HCIPs) in HEK293T cells and 352 HCIPs in MCF10A cells. We subsequently focused on a neuron-specific CDK, CDK5, and uncovered two novel CDK5-binding partners, KIAA0528 and fibroblast growth factor (acidic) intracellular binding protein (FIBP), in non-neuronal cells. We showed that these three proteins form a stable complex, with KIAA0528 and FIBP being required for the assembly and stability of the complex. Furthermore, CDK5-, KIAA0528-, or FIBP-depleted breast cancer cells displayed impaired proliferation and decreased migration, suggesting that this complex is required for cell growth and migration in non-neural cells. Our study uncovers new aspects of CDK functions, which provide direction for further investigation of these critical protein kinases. Molecular & Cellular

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confidence: 99%

Proteomic Analysis of the Human Cyclin-dependent Kinase Family Reveals a Novel CDK5 Complex Involved in Cell Growth and Migration

Wang

et al. 2014

Molecular & Cellular Proteomics

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“…The identified Ser20 site on CHIP resides in (S/T)PX(K/R), the highly conserved consensus sequence for the phosphorylation across species (Supplementary Figure 2). [19][20][21] To further confirm whether Cdk5 phosphorylates CHIP at Ser20 in vivo, we raised a rabbit polyclonal antibody and confirmed its specificity (Supplementary Figure 3). Indeed, this antibody detected the phosphorylated CHIP at Ser20 in HEK293 cells expressing both HA-CHIP WT and Flag-Cdk5/p25-Myc (Figure 1f).…”

Section: Resultsmentioning

confidence: 95%

Phosphorylation of CHIP at Ser20 by Cdk5 promotes tAIF-mediated neuronal death

et al. 2015

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Cyclin-dependent kinase 5 (Cdk5) is a proline-directed serine/threonine kinase and its dysregulation is implicated in neurodegenerative diseases. Likewise, C-terminus of Hsc70-interacting protein (CHIP) is linked to neurological disorders, serving as an E3 ubiquitin ligase for targeting damaged or toxic proteins for proteasomal degradation. Here, we demonstrate that CHIP is a novel substrate for Cdk5. Cdk5 phosphorylates CHIP at Ser20 via direct binding to a highly charged domain of CHIP. Co-immunoprecipitation and ubiquitination assays reveal that Cdk5-mediated phosphorylation disrupts the interaction between CHIP and truncated apoptosis-inducing factor (tAIF) without affecting CHIP's E3 ligase activity, resulting in the inhibition of CHIPmediated degradation of tAIF. Lentiviral transduction assay shows that knockdown of Cdk5 or overexpression of CHIP S20A , but not CHIP WT , attenuates tAIF-mediated neuronal cell death induced by hydrogen peroxide. Thus, we conclude that Cdk5-mediated phosphorylation of CHIP negatively regulates its neuroprotective function, thereby contributing to neuronal cell death progression following neurotoxic stimuli.

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“…Indeed, in recent years, novel regulatory proteins such as cyclins I or G have been described, and the activation of CDK5 has been involved in multiple cellular processes. 32,33 Regarding kidney, in podocytes, which are the postmitotic kidney cells responsible for glomerular filtration processes, the involvement of CDK5, p35, and cyclin I in cell survival processes has been demonstrated. 13,16 Double KO mice p35 and cyclin I exhibit a normal kidney phenotype, although glomerular disease induction triggers exacerbated apoptosis activation.…”

Section: Discussionmentioning

confidence: 99%

Role of CDK5/cyclin complexes in ischemia-induced death and survival of renal tubular cells

et al. 2014

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Going out of the brain: Non-nervous system physiological and pathological functions of Cdk5

Cited by 82 publications

References 126 publications

Proteomic Analysis of the Human Cyclin-dependent Kinase Family Reveals a Novel CDK5 Complex Involved in Cell Growth and Migration

Proteomic Analysis of the Human Cyclin-dependent Kinase Family Reveals a Novel CDK5 Complex Involved in Cell Growth and Migration

Phosphorylation of CHIP at Ser20 by Cdk5 promotes tAIF-mediated neuronal death

Role of CDK5/cyclin complexes in ischemia-induced death and survival of renal tubular cells

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