AKT and Apoptosis

Aimee Catherine McLeanMay 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– Encoded in c-Akt protooncogene– mediates growth factor receptor-

generated survival signals – Critical for neuronal survival

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

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

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- that ultimately leads to NF- activation and cell survival.

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- that ultimately leads to NF- activation and cell survival.

• Activates eNOS, involved in Nitrous Oxide production and is linked to long term blood vessel growth (esp important in angiogenesis)

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

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

                                   

                                                                 

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

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

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

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

Ovarian Cancer• Akt-2 is over expressed in 10-20%

of ovarian cancer cases

Renal TroubleElevated levels of Akt phosphorylation indicate renal tubular stress

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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