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- The Discovery of Protein Phosphorylation
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1. Phosphorylase and the origin of reversible protein phosphorylation
- Prof. Edmond Fischer
- Protein Kinase Cascades
- The Modulation of Protein Function by Phosphorylation
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4. Two is the key to 14-3-3: dimeric mechanical signaling devices
- Prof. Carol MacKintosh
- Protein Phosphatases
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5. Structure and mechanisms of protein phosphatases
- Prof. David Barford
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6. Protein tyrosine phosphatases
- Prof. Jack Dixon
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7. The regulation of MAP kinase signalling by dual-specificity protein phosphatases
- Prof. Steve M. Keyse
- The Structures of Protein Kinases
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9. Protein kinase structure, function and regulation
- Prof. Susan Taylor
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10. The structural basis for the modulation of protein function by protein phosphorylation
- Prof. Dame Louise N. Johnson
- Biological Systems that are Regulated by Reversible Phosphorylation
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11. Protein phosphorylation and the control of protein synthesis
- Prof. Christopher Proud
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13. Roles of AMPK in energy homeostasis and nutrient sensing
- Prof. Grahame Hardie
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14. Serine kinases and T lymphocyte biology
- Prof. Doreen Cantrell
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15. The interplay between protein phosphorylation and ubiquitylation in the NF-κB pathway
- Prof. Zhijian 'James' Chen
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16. SMAD phosphorylation and the TGF-beta pathway
- Prof. Joan Massagué
- Protein Kinases and Human Disease
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17. Function and regulation of the PDK1 kinase
- Prof. Dario Alessi
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18. LKB1 pathway and its role in cancer
- Prof. Dario Alessi
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19. WNK1 pathway and its role in regulating hypertension
- Prof. Dario Alessi
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20. The hyperphosphorylation of tau and Alzheimer's disease
- Prof. Michel Goedert
- Protein Kinases as Targets for the Development of Anti-Cancer Drugs
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21. PI3K/AKT signaling in cancer
- Prof. Neal Rosen
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22. RAS and RAF signaling in melanoma: biology and therapies
- Prof. Richard Marais
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23. The mTOR kinase as a target for anti-cancer drugs
- Prof. David Sabatini
- Archived Lectures *These may not cover the latest advances in the field
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25. AMP-activated protein kinase: regulating cellular and whole body energy balance
- Prof. Grahame Hardie
Printable Handouts
Navigable Slide Index
- Introduction
- Insulin
- Insulin cascade
- Approaches to study the insulin signalling pathway
- Insulin pathway (1)
- GSK3 regulates glycogen synthase by insulin
- PI3K inactivates GSK3 (1)
- PI3K inactivates GSK3 (2)
- GSK3 inactivation by other kinases
- Protein Kinase B (Akt)
- PKB signal transduction
- Substrate specificity of PKB
- Insulin activates PKB
- PKB is phosphorylated on Thr308 and Ser473
- PKB phosphorylation on the catalytic domain
- Insulin locates PKB to the plasma membrane
- PKB translocation to the cell membrane
- PKB translocation is important for its activation
- Mechanism of PKB activation
- Which kinase phosphorylates PKB?
- Discovery of PDK1
- Primary structure of human PDK1
- PIP3 is required for PDK1 activation of PKB
- PDK1/2 phosphorylate PKB
- PIP3 does not activate PDK1 in vitro
- Molecular mechanism by which PKB is activated
- Muscle-specific knockouts of PDK1 (1)
- Muscle-specific knockouts of PDK1 (2)
- No insulin activation of PKB in knockout mice
- No phosphorylation of PKB in knockout mice
- Insulin pathway (2)
- No phosphorylation of GSK3 in knockout mice
- Glycogen synthase inactivation by GSK3
- No dephosphorylation of GS in knockout mice
- GSK3 knock-in mice (1)
- GSK3 knock-in mice (2)
- Analysis of GSK3 isoforms in knock-in mice
- Glycogen synthase activity in knock-in mice
- Summary (1)
- Insulin effects are mediated by protein kinases
- S6K, SGK and PKC activation
- PDK1 is a "master upstream kinase"
- No insulin activation of S6K knockout PDK1 mice
- Genetic evidence that PDK1 is a master kinase
- PDK1 activates 24 of the AGC kinase members
- Regulation of the PDK1 pathway
- PDK1 kinase domain
- Defining the PIF-pocket by knock-in mutation
- S6K is not activated in PDK1 PIF-pocket KI mice
- The role of PIP3 binding to the PH domain (1)
- The role of PIP3 binding to the PH domain (2)
- Is PKB activated in the knock-in cells?
- PKB is inhibited in PDK1 PH domain KI cells
- Summary (2)
- The role of the PDK1 in cancer
- Evaluation of PDK1 as a drug target
- Generation of PDK1 hypomorphic mice
- PTEN
- PTEN effect in cancer
- Summary of tumours
- Conclusions
- Acknowledgements
- Sunset over the Tay bridge
Topics Covered
- Physiological functions and signaling pathways of insulin
- Role of GSK3 in the insulin signaling cascade
- Regulation of GSK3 by insulin via PI3K and PKB/Akt
- PKB as a key mediator of insulin signaling responses
- Exploring the mechanism of PKB activation by PI3K and PDK1
- Molecular mechanism of PKB activation
- exploring the role of PDK1 in GSK3 regulation by insulin
- Studying the model of GSK3 regulation in vivo
- Insulin effects mediated by several protein kinases
- PDK1 as a "master upstream kinase"
- Regulation of the PDK1 pathway
- The physiological role of PIP3 binding to PDK1
- The role of the PDK1 in cancer
- Evaluation of PDK1 as a drug target for the treatment of cancer
Talk Citation
Alessi, D. (2010, December 14). Function and regulation of the PDK1 kinase [Video file]. In The Biomedical & Life Sciences Collection, Henry Stewart Talks. Retrieved January 15, 2025, from https://doi.org/10.69645/TCZJ9813.Export Citation (RIS)
Publication History
Financial Disclosures
- Prof. Dario Alessi has not informed HSTalks of any commercial/financial relationship that it is appropriate to disclose.
A selection of talks on Biochemistry
Transcript
Please wait while the transcript is being prepared...
0:00
Hello there. A very big welcome to my Henry Stewart talk.
My name is Dario Alessi and in today's lecture,
I'm going to tell you about the work that my laboratory has done on
the PDK1 protein kinase over the last 15 years or so.
This work was done in one of the best places in
the world to study signal transduction pathways
of the protein phosphorylation units at the University of Dundee.
So my talks are going to be divided into different sections.
And first I'm going to give you
a very general introduction to Insulin and Insulin signaling.
And then, I'm going to tell you about the work that led up to
the discovery of PDK1 and the subsequent analysis,
that we have done on this enzyme,
to show the central role it plays in
Insulin and growth factor receptor signalling pathways.
And then, I'll finish this talk by telling you about
some research that indicates that inhibiting PDK1,
may be a very useful strategy to treat or better treat many types of cancer.
1:04
Insulin is a hormone secreted by the beta cells of the pancreas,
following food ingestion by animals.
Its main function is to stimulate the uptake of nutrients such as glucose,amino acids,
fatty acids into tissues and stimulate
their conversion into the stable macromolecules such as glycogen,
protein and lipids, that can be used as a fuel source,
to fuel the cells' and tissues' activities.
And Insulin mainly exerts these effects in
the key insulin sensitive tissues of the body which are skeletal muscle,
adipose and liver tissues.
The way Insulin works is by binding to the Insulin receptors,