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AKT and Apoptosis

AKT and Apoptosis. Aimee Catherine McLean May 12, 2003. Outline. Introduction: What and Why The Pathway: Overview and Detailed Related Diseases and Akt’s Role Summary . What is Akt?. Also called Protein Kinase B (PKB) Akt 1 is a serine/threonine kinase Downstream effector of PI 3-kinase

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AKT and Apoptosis

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  1. AKT and Apoptosis Aimee Catherine McLean May 12, 2003

  2. Outline • Introduction: What and Why • The Pathway: Overview and Detailed • Related Diseases and Akt’s Role • Summary

  3. What is Akt? • Also called Protein Kinase B (PKB) • Akt 1 is a serine/threonine kinase • Downstream effector of PI 3-kinase • Encoded in c-Akt protooncogene • mediates growth factor receptor-generated survival signals • Critical for neuronal survival

  4. What is Akt? • Akt 2 is a general kinase • Capable of phosphorylating many different proteins • data indicate that AKT-2 mediates PI3-K-dependent effects on adhesion, motility, invasion, and metastasis in vivo

  5. Why is it Important? • Involved in normal cell growth • Glucose regulation, NO synthesis, Related to many growth factors • Causes tumors when over expressed • Implicated in many diseases: • Huntington’s disease • Leukemia • Ovarian Cancer

  6. The Pathway in Brief • Surface receptors  production of second messengers that activate PI3K  PI3K generates phosphorylated phosphatidylinositides PI(3,4)P2 and PI(3,4,5)P3 in the cell membrane that bind to PH domain of Akt  PI(3,4)P2 and PI(3,4,5)P3 activate phosphoinositide-dependent kinase (PDK) which phosphorylates membrane-bound Akt Akt inhibits apoptosis by phosphorylating the Bad component of the Bad/Bcl-XL complex Akt activates IKK-a that ultimately leads to NF-kb activation and cell survival.

  7. Akt Promotes Cell Survival Through Multiple Pathways • Inhibits apoptosis by phosphorylating the Bad component of the Bad/Bcl-XL complex. Phosphorylated Bad binds to 14-3-3 causing dissociation of the Bad/Bcl-XL complex and allowing cell survival. (Prevents Bad from going to mitochondria to initiate apoptosis) • Activates IKK-a that ultimately leads to NF-kb activation and cell survival. • Activates eNOS, involved in Nitrous Oxide production and is linked to long term blood vessel growth (esp important in angiogenesis)

  8. Inhibition Pathways Continued… • Akt-1 prevents apoptosis through phosphorylation of caspase 9 • Disrupts association of Tpl-2 and Tvl-1 with apoptosome complex • Inhibits forkhead transcription factors which prevents the forkheads from transcribing the proapoptotic protein Fas • Activates TERT (responsible for maintenace of Telomeres and, thus, DNA stability

  9. A Bit More Detailed… • Receptor Tyrosine Kinase activates PI3K which then phosphorylates PI(4,5)P2 (membrane-bound) at C3 of the inositol ring generating PI(3,4,5)P3 which has a high affinity for Akt and PDK1 • Akt becomes anchored to membrane, phosphorylated and activated by PDK1 at Threonine 308 and Serine 473 • PI(3,4,5)P3 binds to pleckstrin homology (PH) on Akt

  10. Akt Regulation • Activation of AKT negatively regulated by PTEN and SHIP • PTEN is a PIP3 specific phosphatase that converts PI(3,4,5)P3 into PI(4,5)P2 • SHIP is an inositol 5’ phosphatase that hydrolyzes PI(3,4,5)P3 to PI(3,4)P2

  11. Glucose Regulation • Enhances glucose uptake • Induces expression of GLUT1 and GLUT3 and causes GLUT4 to move to membrane • Inactivates GSK-3 via phosphorylation that then activates glycogen synthase • Enhances glycolysis • PFK2  PFK1 via phosphorylation • Fructose-6-P  Fructose 1,6-bisphosphate

  12. Huntington’s Disease • Neurodegenerative disease with mid-life onset • Autosomal Dominant Inheritance • Characterized by involuntary movements (chorea), short term memory loss, loss of coordination • Neuronal death in striatum and cerebral cortex

  13. Leukemia • MAPK signal transduction cascade • PI 3-kinase/Akt Pathway is essential for BCR/ABL leukemogenesis • Leukemia suppressed when Akt is inhibited • Akt activates c-Myc and Bcl-2 expression

  14. Ovarian Cancer • Akt-2 is over expressed in 10-20% of ovarian cancer cases Renal Trouble Elevated levels of Akt phosphorylation indicate renal tubular stress

  15. Sources • 1. Gruver, Markova, Patriotis & Querec. "Regulation of Signal Transduction and Changes in Patterns of Gene Expression in Breast and Ovarian Cancer" Medical Science Division. • 2. "Signal Transduction Via Fc Receptors," <http://www.idac.tohoku.ac.jp/dep/expimu/FcRsignal.html> • 3. "Hot Papers in Signal Transduction," The Scientist. May 1999 <http://www.the-scientist.com/yr1999/may/hot1_990524.html> • 4. Sandou, Frédéric. "Signal Transduction and Neuronal Death," <http://www.curie.fr/sr/cdrom/equipes/saude.html> • 5. Skorski et. al. "Transformation of Hematopoietic Cells by BCR/ABL Requires Activation of a PI-3k/Akt-dependent Pathway," EMBO Journal Vol. 16 No. 20 pp. 6151-6161, 1997. Oxford University Press. < http://emboj.oupjournals.org/cgi/content/full/16/20/6151> • 6. Nishino et al. "Elevated Akt Phosphorylation as an Indicator of Renal Tubular Epithelial Stress," Journal of Biological Chemistry, Vol. 277, Issue 37, 33943-33949, September 13, 2002. < http://www.jbc.org/cgi/content/full/277/37/33943>

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