Presentation is loading. Please wait.

Presentation is loading. Please wait.

AMPK – Akt – mTOR AXIS IS A METABOLIC CHECKPOINT OF THE CELL

Published byMarjorie Alexander Modified over 6 years ago

Similar presentations

Presentation on theme: "AMPK – Akt – mTOR AXIS IS A METABOLIC CHECKPOINT OF THE CELL"— Presentation transcript:

1 AMPK – Akt – mTOR AXIS IS A METABOLIC CHECKPOINT OF THE CELL
in normal and malignant cells AMPK – Akt – mTOR AXIS IS A METABOLIC CHECKPOINT OF THE CELL Dr. Tomas Koltai

2 HISTORY STARTS IN RAPA NUI (isla de Pascua) (Easter Island)
Where Streptomyces hygroscopicus, a bacteria, was found in the soil. It elaborated a product that showed strong antifungal activity, besides immunosuppression and inhibition of cell proliferation. This product was named RAPAMYCIN

3 Looking for the molecular site of action of RAPAMYCIN
A protein was identified in the cell which was called TARGET OF RAPAMYCIN (or TOR). Nowadays it is mTOR (mammalian target of rapamycin) Heitman J, Mowa NR, Hall MN, (1991) Science 253:

4 Rapamycin is a powerful inhibitor of mTOR
But it does not act alone. It forms a complex with other protein: FKBP12. This complex of rapamycin and FKPB12 binds to mTOR and inhibits it. mTOR FKBP12 RAPAMYCIN INACTIVATION OF mTOR

5 ...is precisely the inhibition of the phosphokinase mTOR
The mechanism that allows rapamycin to produce immunosuppressive, antiproliferative and antifungal activity… ...is precisely the inhibition of the phosphokinase mTOR Rapamycin

6 mTOR proteins Are big size proteins (280 Kd).
Present in all eucariotic cells. Have phosphokinase activity. There are two different mTORs in mammals: mTOR1 and mTOR2 forming two different associations with other proteins: mTOR1 + RAPTOR = mTORC1 mTOR2 + RICTOR = mTORC2

7 mTor and its inhibition by the FKBP12-rapamycin complex

8 mTORC1 is inhibited by rapamycin
mTORC2 shows little or no response to rapamycin inhibition. But if it is administered for a long time, some inhibition may appear.

9 All previous steps are absolutely necessary for cell proliferation.
Actions of mTORC1 Has a role in protein synthesis. Induces ribosomal biogenesis. Stimulates RNAm translation. Checks nutrient and energy availability All previous steps are absolutely necessary for cell proliferation.

10 Cell may undergo autophagy through inhibition of mTOR.
If the requiered nutrients or energy are not available… Cell may undergo autophagy through inhibition of mTOR. GENOMIC STRESS AMP ATP AMPKinase mTOR P53 mTOR is an inhibitor of autophagia AUTOPHAGIA

11 mTOR is a metabolic regulator of the cell
Regulators of mTOR activities Growth factors Nutrients Energy Stress Hypoxia

12 GROWTH FACTORS REGULATING mTOR IRS PI3K AKT TSC2 TSC1 Rheb mTORC1
IGF Extracellular Cell Membrane IGFR IRS PI3K Intracellular AKT GROWTH FACTORS REGULATING mTOR TSC2 TSC1 Rheb RICTOR RAPTOR mTORC1 TRANSCRIPTION mTORC2 AUTOPHAGIA S6K E4 BP ACTINE ORGANIZATION PROTEIN SYNTHESIS RIBOSOMAL GENESIS

13 HYPOXIA REGULATING mTOR HIPOXIA TSC2 HIF TSC1 Rheb mTORC1 mTORC2
Cell Membrane Extracellular cytoplasm HYPOXIA REGULATING mTOR REDD1 Y REDD2 HIPOXIA TSC2 HIF TSC1 Rheb RICTOR RAPTOR mTORC1 mTORC2

14 STRESS REGULATING mTOR STRESS: Due to DNA damage P53 activation TSC2
AMPK activation TSC1 Rheb RICTOR RAPTOR mTORC1 TRANSCRIPCION mTORC2

15 Nutrient availability REGULATING mTOR
NUTRIENTS Nutrient availability REGULATING mTOR Cell Membrane Rheb mTORC1 RICTOR RAPTOR TRANSCRIPTION mTORC2 AUTOPHAGIA S6K E4 BP ACTIN ORGANIZATION RIBOSOMAL BIOGENESIS PROTEIN SYNTHESIS

16 ENERGY REGULATING mTOR INCREASED AMP/ATP RATIO LOW ENERGY AVAILABLE
TSC2 AMPK TSC1 LKB1 Rheb RICTOR RAPTOR mTORC1 mTORC2

17 MAPKINASES ACTIVATION REGULATING mTOR
Membrane ACTIVATION OF RAS-MAPK PATHWAY MAPKINASES ACTIVATION REGULATING mTOR TSC2 TSC1 Rheb RICTOR RAPTOR mTORC1 mTORC2

18 AMPK – Akt – mTOR pathway is a metabolic check point

19 Mechanism of the metabolic check point
mTORC1 is activated when AMPK activity is decreased. AMPK is activated when the AMP/ATP ratio increases (which means low energy). Activated AMPK decreases all those activities that are energy demanding through inhibition of mTORC1 by two pathways.

20 Mechanism of check point in simple words
AMPK “informs” mTOR if there is enough energy. If there is enough energy, mTOR stimulates protein synthesis and proliferative activity. If tehre is energy shortage, mTOR is deactivated and there is no synthesis nor proliferation. In extreme cases, autophagia is started.

21 What is AMPK? It is a serine/treonine kinasa that senses available celular energy. It is activated by metabolic stress like physical exercise, hypoxia, glucose decrease, etc. It is regulated by AMP/ATP ratio and by kinases LKB1 and CaMKKbeta (calmodulin dependent protein kinase kinase beta). The activaction of AMPK suppresses metabolic activities that requiere ATP and increases those that generate ATP.

22 DOUBLE MECHANISM of mTOR INHIBITION BY AMPK:
THROUGH STIMULATING TUBEROUS SCLEROSIS COMPLEX DIRECT INHIBITION OF mTORC1 LKB1 OTHER ACTIVATORS OF AMPK: resveratrol, quercetina,berberine. INCREASED AMP/ATP RATIO TSC2 AMPK TSC1 METFORMIN Rheb RAPTOR mTORC1 Gwinn DM et al. Mol Cell (2):

23 Akt DOUBLE MECHANISM OF SELENIUM ON THE METABOLIC CHECKPOINT
STIMULATION/ACTIVATION OF AMPK DIRECT INHIBITION OF Akt LKB1 TSC2 AMPK SELENIO TSC1 Rheb RAPTOR mTORC1 Akt Lee YK et al. Carcinogenesis 2010; 31(6):

24 Incresead AMP/ATP ratio LKB1 CaMKK
Calcium Abundance Incresead AMP/ATP ratio LKB1 CaMKK Other kinases Decreased fatty acid synthesis EF2K Decreased protein synthesis AMPK ACC1/FAS TSC2 ACC2 HMG-Co A reductase p53 Increased fatty Acid oxidation Decreased colesterol synthesis mTOR Cell cycle arrest Fay JR et al. Cancer Prev Res 2009;2(4): (ACC: acetilCoa carboxilasa/ HMG-Co A: hidroximetilglutaril-Co a reductasa)

25 ANTAGONISTIC ACTIVITIES BETWEEN Akt and AMPK: central axis of energetic control
FOXO PI3K AMPK Akt TSC2 TSC1 RHEB-GTP RAPTOR PRAS40 mTOR mTORC1 GBL

26 Deactivators of mTORC1 Lack of environmental amino acids (particularly leucine) Decreased energy (via AMPK) Hypoxia (via REDD1 y REDD2 and HIF) Stress (hypoxia, DNA damage through P53) Drugs: rapamycin, metformin, AICAR

27 The circuit 1) Negative biofeedback from TSC-mTORC1-S6K1 on the pathway IRS-PI3K-Akt This biofeedback is important in diabetes and obesity. It also explains the failure in cancer treatment of certain tumors with rapamycin and rapalogs. 2) mTORC2 activates Akt Akt activation is an important step in cancer.

28 Diferences and similarities between rapamycin and metformin actions on this check point
Inhibits mTOR Increases Akt activity by the negative feedback circuit Decreases negative feedback on IRS1 Acts directly on Raptor METFORMIN Inhibits mTOR Does not increase Akt activity Does not Acts indirectly through AMPK Zakikhani M et al Breast Cancer Res Treat. 5 february 2010

29 AMPK and Raptor: Matching Cell Growth to Energy Supply Interaction Raptor-AMPK Growth is dependent on cellular energy Hardy DG. Molecular Cell 30, May 9, 2008;

30 LKB1-AMPK-mTORC1 and metformin
LKB1: liver kinase B 1 AMPK: adenosine monophosphate activated protein kinase mTORC1: mammalian target of rapamicine complex 1 AMPK is activated by phosphorylation dependent on LKB1 If LKB1 is inhibited AMPK remains inactive. LKB1 inhibition produces hyperglycemia with increased gluconeogenesis yand lipogenesis. LKB1’s activity is necessary for AMPK activation under energy stress (decreased ATP and increased AMP). Metformin requieres a functioning LKB1 for its glucose lowering activity. If LKB1 is absent, metformin lacks glucose lowering activity. According to Rocha metformin may activate AMPK even when LKB1 is absent. Shaw RJ et al. Science 2005; 310(5754): Rocha GZ. Clini Cancer Res 2011;17:

31 AMPK and cancer: 2 contradictions
Under isquemia, AMPK activates PFK-2(phosphofructokinase) La PFK-2 protects cells against isquemia. Malignant cells have high levels of PFK-2. CONCLUSION AMPK may protect tumor cells against isquemia. On the other side, it decreases protien synthesis through inhibition of mTORC1.

32 AMPK activators in cancer may produce
Growth arrest of malignant cells with increased expression of P53 and CDK inhibitors like P21 y P27. 1) Rattan et al. J Biol Chem 2005;280: // 2) Imamura et al. Biochem Biophys Res Commun 2001;287:562-7// 3) Xiang X et al Biochem Biophys Res Commun 2004;321:161-7 Inhibition of breast cancer cells growth with decreased protein synthesis and inhibition of mTOR (Zakikhani et al. Cancer Res 2006;66: ) Inhibition of growth of p53 deficient tumor cells. Buzzai et al. Cancer Res 2007;67: Delayed tumor growth and smaller size. Anisimov et al Exp Gerontol 2005;40:685-93 Preventive action in the development of experimental tumors. Schneider et al. Gastroenterology 2001;120: Retarded tumor growth. Huang et al Biochem J, 2008;412:

33 Akt’s activity in cell metabolism control

34 Akt Stimulates glycolysis Induces resistance to apoptosis
Activates hexokinase Through GSK3 (glycogen synthase kinase 3) produces translocation of hexokinase to mitochondrial membrane where it binds to the voltage dependent annion channel (VDAC) suppressing apoptosis.

Download ppt "AMPK – Akt – mTOR AXIS IS A METABOLIC CHECKPOINT OF THE CELL"

Similar presentations

Metabolism and Cancer Bob Harris D-3034 Roudebush VA Medical Center 988-4544 Fall 2010.

Metabolism and Cancer Bob Harris D-3034 Roudebush VA Medical Center Fall 2010.
Insulin Signaling – Insulin Resistance Elmus G. Beale, Professor Texas Tech University Health Sciences Center Paul L. Foster School of Medicine PhD, Baylor.

Insulin Signaling – Insulin Resistance Elmus G. Beale, Professor Texas Tech University Health Sciences Center Paul L. Foster School of Medicine PhD, Baylor.
Targeting the IGF Pathway in Pediatric Sarcomas-Lessons Learned and Questions Raised Lee J. Helman, M.D. Scientific Director for Clinical Research,Center.

Targeting the IGF Pathway in Pediatric Sarcomas-Lessons Learned and Questions Raised Lee J. Helman, M.D. Scientific Director for Clinical Research,Center.
Hypertrophic signalling Identify contraction-induced growth signals Describe the composition and regulation of mTORC1 Describe the effectors of mTOR Explain.

Hypertrophic signalling Identify contraction-induced growth signals Describe the composition and regulation of mTORC1 Describe the effectors of mTOR Explain.
Bio 714 Foster TGF-beta/cell cycle material. Points: Suppression of either PLD or mTOR in the absence of serum results in apoptosis Importantly, suppression.

Bio 714 Foster TGF-beta/cell cycle material. Points: Suppression of either PLD or mTOR in the absence of serum results in apoptosis Importantly, suppression.
Restriction Point G0 TGF-  and Cell Cycle Progression Cyclin D CDK4/6 Cyclin E CDK2 TGF-  Cell Growth Checkpoint G1-pm SG1-psG2M.

Restriction Point G0 TGF-  and Cell Cycle Progression Cyclin D CDK4/6 Cyclin E CDK2 TGF-  Cell Growth Checkpoint G1-pm SG1-psG2M.
Insulin and Amino Acid Signaling Through mTOR in Perfused Rat Liver Jessica Biegler.

Insulin and Amino Acid Signaling Through mTOR in Perfused Rat Liver Jessica Biegler.
Date of download: 6/21/2016 Copyright © 2016 American Medical Association. All rights reserved. From: Improving Glucose Metabolism With Resveratrol in.

Date of download: 6/21/2016 Copyright © 2016 American Medical Association. All rights reserved. From: Improving Glucose Metabolism With Resveratrol in.
Catchy LKB1 Title Abstract Billions of dollars are being poured into the research of cancer, the National Cancer Institute alone spends $4.9 Billion every.

Catchy LKB1 Title Abstract Billions of dollars are being poured into the research of cancer, the National Cancer Institute alone spends $4.9 Billion every.
Catchy LKB1 Title Abstract Billions of dollars are being poured into the research of cancer, the National Cancer Institute alone spends $4.9 Billion every.

Catchy LKB1 Title Abstract Billions of dollars are being poured into the research of cancer, the National Cancer Institute alone spends $4.9 Billion every.
Regulation of glucose levels in the blood is very important Normal Fasting (Serum) ~ 70 – 100 mg/dl Elevated = Diabetes Low = Hypoglycemia Insulin from.

Regulation of glucose levels in the blood is very important Normal Fasting (Serum) ~ 70 – 100 mg/dl Elevated = Diabetes Low = Hypoglycemia Insulin from.
Cellular hypertrophy Control of protein accretion –Endogenous Nutrient status Functional adequacy History –Exogenous Nutrient availability Growth factors.

Cellular hypertrophy Control of protein accretion –Endogenous Nutrient status Functional adequacy History –Exogenous Nutrient availability Growth factors.
Kate Bradford BIOL 445 March 5, 2009

Kate Bradford BIOL 445 March 5, 2009
Study on mTOR-regulated GLUT4 Translocation

Study on mTOR-regulated GLUT4 Translocation
AMPK—Sensing Energy while Talking to Other Signaling Pathways

AMPK—Sensing Energy while Talking to Other Signaling Pathways
MYC, Metabolism and Cancer

MYC, Metabolism and Cancer
Strategies for differential inhibition of mTORC1 and mTORC2 with rapamycin. Strategies for differential inhibition of mTORC1 and mTORC2 with rapamycin.

Strategies for differential inhibition of mTORC1 and mTORC2 with rapamycin. Strategies for differential inhibition of mTORC1 and mTORC2 with rapamycin.
Selective interference of mTORC1/RAPTOR protects against human disc cellular apoptosis, senescence, and extracellular matrix catabolism with Akt and autophagy.

Selective interference of mTORC1/RAPTOR protects against human disc cellular apoptosis, senescence, and extracellular matrix catabolism with Akt and autophagy.
IRS-1: Auditing the effectiveness of mTOR inhibitors

IRS-1: Auditing the effectiveness of mTOR inhibitors
Figure 1 mTOR pathway activation

Figure 1 mTOR pathway activation

Similar presentations

Ads by Google