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Time: 2/26/08
Speaker: Harish C. Pant; NIH,Bethesda, MD
Title: "Cyclin Dependent Kinase 5 (Cdk5): Regulation of Neuronal Cytoskeletal Protein Phosphorylation and Stem Cell Differentiation/Neurogenesis."
1. Cytoskeletal protein phosphorylation occurs only in axon.
2. All enzymes are synthesized in the head.
3. Neuron cytoskeletal protein phosphorylations are topographically and tightly regulated under physiological conditions.
4. SMI-31 selectively stain the phosphorylated sites.
5. Proline-directed Ser/Thr-phosphorylation of neuronal cytoskeletal proteins leads to conformational change in physiological and pathological processes.
6. consensus sequence: KSP repeats
7. Tau proteins form plaques and tangles.
8. Why phosphorylation only happens in the axon, and what's the mechanism of it?
9. Cdk5--> is a kinase in Cdk family; not activated by a cyclin; binds with cyclin D/E; activity found primarily in neurons; activated by neuron specific molecules: P35&P39 (P35 is the major activator).
10. When Cdk5 is deregulated, P35 gets cleaved, and nothing happens to the Cdk5.
11. Consensus sequence of Cdk5 phosphorylation activity: XS/TPYK/R (X:any a.a.; Y: basic or neutral a.a.) (VKSPAKEKASPEK)
12. Cdk5 (-/-) mice: aberrant and higher phosphorylation of neuronal cytoskeletal proteins; reduced PI3K activity and higher MAPKS (Erk1/2) and SAPKS (JNKS) activity inducing apoptosis.
13. Cdk5 regulates neuronal survival: Cdk5 cross-talk with PI3K.
14. P35 anchors Cdk5 to the membrane.
15. Cdk5 regulates neurogulin-medicated ErBRs PI3K/Akt survival pathway.
16. Lipid phosphorylation and PI3K and Akt activity is reduced in Cdk5 (-/-) mice brain.
17. ErbB3-Ser/Thr-phosphorylation is reduced in Cdk5 (-/-) mice brain.
18. Neurogulin-induced Akt phos/activation is reduced by Cdk5 and PI3K inhibitors in cortical neurons.
19. Roscovitine--> inhibitor of Cdk5
20. Cdk5 modulates MAPK activity and neuronal survival.
21. Inhibition of Cdk5 sustained Erk1/2 activation-->produced cell death in cortical neurons.
22. Inhibition of Erk1/2 reduced apoptosis in Roscovitine treated neurons.
23. Cdk5 cross talk with JNK3
24. Cdk5 phosphorylates JNK3 and inhibits JNK3 activity
25. Elevated c-Jun phosphorylation in the absence of Cdk5
26. Cdk5 involves in diseases like Alzheimer's disease and Amyotrophic lateral sclerosis.
27. Cdk5 also plays a role in stem cell differentiation.
28. Neural stem cells have the capacity for self-renewal and differentiation into multiple cell types.
29. Method to isolate neural stem cells-->cell sorting.
30. Absence of Cdk5 did not produce apoptosis to NSC during proliferation.
31. What happened to differentiation? p27Kip colocalize and binds with p35 and Cdk5 in NSC.
32. Cdk5 phosphorylates p27Kip1 (T187)
33. Phosphorylation of p27Kip1 by Cdk5 regulates neural stem cell differentiation-->cdk5 phosphorylates p27Kip1, and inhibits its degradation (stabilizes) and induces neurogenesis/differentiation.
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