CDK5 Human
Description
Regulatory Mechanisms
CDK5 activity is tightly regulated by activators, inhibitors, and post-translational modifications:
Activators
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p35/p25 and p39/p29: Primary activators that bind CDK5, enabling substrate phosphorylation. p35’s myristoylation localizes CDK5 to membranes, while calpain-mediated cleavage of p35 to p25 releases CDK5 into the cytoplasm, prolonging its activity .
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Cyclin I: Promotes nuclear CDK5 activity and upregulates anti-apoptotic proteins Bcl2/Bcl2l1 via MEK/ERK signaling .
Inhibitors
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Cyclin D1/D3: Compete with p35 for CDK5 binding, forming inactive complexes and reducing kinase activity .
Phosphorylation
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p35 phosphorylation: At Thr138 prevents calpain cleavage, maintaining CDK5’s neurodevelopmental roles during fetal stages .
Central Nervous System
CDK5 governs neuronal migration, axon guidance, and synaptic function:
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Cytoskeletal organization: Phosphorylates neurofilament heavy chain (NF-H) to promote neurofilament assembly and stabilizes CRMP2A via Pin1 to support growth cone dynamics .
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Cell cycle suppression: Nuclear CDK5 inhibits neuronal cell cycle re-entry, critical for maintaining postmitotic states. Loss of nuclear CDK5 correlates with Alzheimer’s disease (AD) pathology .
Immune System
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T-cell activation: Phosphorylates coronin 1a to regulate actin polarization and enhances IL-2 production by disrupting HDAC1/mSin3a repression .
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PD-L1 regulation: Upregulates PD-L1 in cancer cells by repressing IRF2/IRF2BP transcription factors .
Cancer Progression
CDK5 drives tumorigenesis in colorectal cancer (CRC), lung cancer, and pancreatic cancer:
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Proliferation: Silencing CDK5 arrests CRC cells at G1/S-phase, while overexpression accelerates cell cycle progression .
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Metastasis: Promotes invasion via ERK5–AP-1 signaling (phosphorylates ERK5 at Thr732) and upregulates oncogenes like VEGFA and MMP1 .
Cell Cycle and Apoptosis
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Cyclin D1 interaction: Attenuates CDK5 activity in postmitotic neurons, linking cell cycle re-entry to apoptosis .
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Anti-apoptotic role: Cyclin I-bound CDK5 enhances Bcl2 expression, promoting cell survival .
Neurodegenerative Diseases
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Alzheimer’s disease: Neurons with cytoplasmic CDK5 (loss of nuclear localization) exhibit cell cycle re-entry and apoptosis, a hallmark of AD .
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Therapeutic target: CDK5 inhibitors (e.g., roscovitine) reduce Aβ-induced neurodegeneration in preclinical models .
Cancer
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Colorectal cancer: High CDK5 expression correlates with advanced AJCC stage, poor differentiation, and reduced survival (median 44 vs. 54 months) .
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Targeted therapy: ERK5 inhibitors (e.g., BIX02189) block CDK5-driven tumor growth and metastasis in CRC models .
Table 1: CDK5 Functions Across Biological Systems
Table 2: Clinical Correlations of CDK5 in CRC
| Parameter | High CDK5 vs. Low CDK5 |
|---|---|
| Median Survival | 44 months vs. 54 months |
| Tumor Size | >5 cm (67% vs. 33%) |
| Lymph Node Metastasis | Present (58% vs. 25%) |
Product Specs
Q&A
What is the primary mechanism by which CDK5 regulates cellular processes in human diseases?
CDK5 primarily functions through kinase activity, phosphorylating downstream targets to modulate signaling pathways. In cancer, CDK5 phosphorylates ERK5 at Thr732, activating the oncogenic ERK5–AP-1 axis to promote CRC progression . In neurodegenerative diseases, CDK5 interacts with p25/p39 activators to regulate neuronal survival, synaptic plasticity, and mitochondrial dynamics . Experimental validation often involves in vitro kinase assays, co-immunoprecipitation (Co-IP), and phospho-specific Western blotting to confirm substrate interactions .
How do researchers address contradictions in CDK5’s dual roles (e.g., neuroprotection vs. neurotoxicity)?
Contradictions arise from context-dependent CDK5 activity. For example, in Huntington’s disease (HD), CDK5 exhibits both neuroprotective and neurotoxic effects depending on activation thresholds and cellular compartments. Researchers resolve this by:
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Cell-type-specific knockdowns: Using shRNA targeting CDK5 in oligodendrocytes vs. neurons to isolate effects .
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Activity thresholds: Measuring phospho-ERK5 levels to distinguish physiological vs. pathological activation .
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Meta-analyses: Integrating data from murine models (e.g., p25 overexpression in Alzheimer’s) and human postmortem brain samples .
What experimental models are most effective for studying CDK5’s role in human diseases?
How is CDK5 implicated in cancer progression, and what therapeutic strategies are being explored?
CDK5 promotes cancer progression via:
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Metastasis: Activating Ras effector proteins (RalA/B) in pancreatic cancer .
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Invasiveness: Phosphorylating cytoskeletal regulators (e.g., paxillin) .
Therapeutic approaches include:
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Small-molecule inhibitors: Roscovitine derivatives targeting CDK5 kinase activity .
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Gene silencing: shRNA-mediated knockdown in orthotopic models .
What are the key CDK5-dependent signaling pathways in neurological and oncological contexts?
How do researchers validate CDK5’s kinase activity in specific signaling pathways?
Validation involves:
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Kinase Assays: In vitro phosphorylation of recombinant substrates (e.g., ERK5, PER2) with purified CDK5/p35 complexes .
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Phosphoproteomics: LC-MS/MS to identify CDK5-specific phosphorylation sites in cellular lysates .
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Genetic Complementation: Rescue experiments in CDK5 knockout cells using constitutively active (CA) or kinase-dead (KD) mutants .
What methodological challenges exist in studying CDK5’s role in neurological vs. oncological contexts?
How do researchers resolve discrepancies in CDK5’s role in circadian rhythm regulation?
Discrepancies often stem from:
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Model variability: Per2 Brdm1 mutants vs. CDK5 knockdown models .
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Temporal dynamics: Diurnal vs. circadian phase-specific effects.
Resolutions include:
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Cross-species validation: Comparing murine SCN data with human fibroblast circadian assays .
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Protein stability analysis: Measuring PER2 degradation rates via cycloheximide chase assays .
What approaches are used to study CDK5’s role in chronic pain mechanisms?
How to interpret CDK5’s dual role in neuroprotection and neurotoxicity in Huntington’s disease?
Interpretation requires:
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Compartmental analysis: Nucleus accumbens (depression) vs. striatal (motor) effects .
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Temporal profiling: Early-stage (depression) vs. late-stage (neurodegeneration) CDK5 activity .
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DARPP-32 phosphorylation status: Assessing Thr75 vs. Thr34 site-specific modifications to infer CDK5 vs. PKA activity .
Product Science Overview
Cdk5 was first discovered due to its sequence homology to the human cell division cycle protein 2 (Cdc2, also known as Cdk1), a key regulator of cell cycle progression . Despite its similarity to other Cdks, Cdk5’s activity is most prominent in post-mitotic neurons, particularly in the adult brain . The kinase activity of Cdk5 is regulated by its association with a non-cyclin protein called p35, which activates Cdk5 upon binding .
Cdk5 is highly expressed in the nervous system, where it phosphorylates a multitude of substrates involved in neuronal proliferation, differentiation, migration, and synaptic plasticity . During brain development, the expression and kinase activity of Cdk5 increase significantly, correlating with the main phase of neuronal differentiation . This kinase is essential for proper brain development and the maintenance of neuronal functions.
There is increasing evidence that aberrant Cdk5 activity is associated with various neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, and Amyotrophic lateral sclerosis (ALS) . Dysregulation of Cdk5 can lead to neuronal damage and death, contributing to the pathogenesis of these diseases. Research has shown that Cdk5 is involved in processes such as mitochondrial dysfunction, oxidative stress, and neuroinflammation, which are common features of neurodegeneration .
Human recombinant Cdk5 is produced using recombinant DNA technology, typically expressed in bacterial systems like E. coli . This recombinant form is used in various research applications to study the kinase’s function, regulation, and involvement in diseases. The availability of human recombinant Cdk5 allows for detailed biochemical and physiological studies, providing insights into its role in health and disease .
