About RAS…By Irsalan Asif and Amy Bunch

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T

K

R

T

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Ras Pathway

SHC

GDP

GTP CD-GEGIIGAP

GTP

Elk1

c-FosATF2

c-Jun

Actin

Cytosk

elet

on

PP P

P

P

P

Stress Fibers and Focal AdhesionsStress Fibers and Focal Adhesions

GeneExpression

GeneExpression

PLDPathway

PLDPathway

PMAPMA

Growth FactorsGrowth FactorsIncreased T Cell

AdhesionIncreased T Cell

Adhesion

IntegrinsIntegrins

β1β1

β2β2 β2β2β1β1β1β1

SOS

p120-GAP

p190-B

Rho

PI3KPLC-ε

Rap1A

PLD RalBP1

PAKs

ERKs

ERKs

JNKK

JNKJNK

MEKK1

CDC42

Rac

MEKs

RafRalGDS

Ral

GRB2

TC

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TC

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AntigenAntigen

LckGEF

Ras Ras

2009ProteinLounge.com 2009ProteinLounge.comC

Sabiosciences.com. Pathway Central: Ras Pathway [Internet]. 2014 [cited 7 December 2014]. Available from: http://www.sabiosciences.com/pathway.php?sn=Ras_Pathway

IntroductionAllows cells to respond to their environment by proliferation, survival and apoptosis.

http://cc.scu.edu.cn/G2S/Template/View.aspx?courseType=1&courseId=17&topMenuId=113301&menuType=1&action=view&type=&name=&linkpageID=113472

This is done by:• Gene transcription• Cell differentiation

About RAS

Conserved GTPase enzyme

Variants: H, K, N and M RAS

Made of 6 β-sheets and 5 α-helices

Alternates between GDP bound (inactive) and GTP bound (active)

http://www.chem.uwec.edu/Modeling/GGProteinStructures/Pages/prs3d08.htm

Failure to Function

Embryonic death in development

Early apoptosis

Cause cancer

Inappropriate differentiation means cells express incorrect proteins

Structure

Rajalingam K, Schreck R, Rapp U, Albert Š. Ras oncogenes and their downstream targets. Biochimica et Biophysica Acta (BBA) - Molecular Cell Research. 2007;1773(8):1177-1195.

MAPKExternal signal

binds to Receptor

Tyrosine Kinase

• Causes autophosphorylation

Recruits Grb-2 and Sos.

• Initiates RAS avtivation. GDP-> GTP bound.

RAF binds to binding domain

on RAS

• Allows subsequent activation of MED and then ERK1/2

Nucleus responds with transcription

Alberts B. Molecular biology of the cell. 5th ed. New York: Garland Science; 2012

PI3K

Active RAS

CAAX

extracellular intracellular

1. Activates p110 PI3K2. Generates PI(4,5)P2 and PI(3,4,5)P3 messengers3. These act as docking sites for serine-threonine

kinases AKT or PKB4. This will inhibit BAD

As a result:• Can cause the protein TOR to stimulate protein synthesis.• Prevents proteolysis.• Induces proliferation.

Alberts B. Molecular biology of the cell. 5th ed. New York: Garland Science; 2012

Regulation of RasNONf1

Le L, Parada L. Tumor microenvironment and neurofibromatosis type I: connecting the GAPs. Oncogene. 2007;26(32):4609-4616.

Tanida S, Mizoshita T, Mizushima T, Shimura T, Kamiya T, Kataoka H et al. Involvement of Cell Proliferation Induced by Dual Intracellular Signaling of HB-EGF in the Development of Colitis-Associated Cancer during Ulcerative Colitis. Ulcers. 2011;2011:1-6.

Drug: Farnesyl transferase inhibitor

• Stops the function RAS’s post-translational modification, (farnesyl isoprenoid group).

• This means RAS cannot attach to the cell membrane.

• Therefore cannot transduce signals.

Study: exposed mouse fibroblast cells to H-RAS• Caused the cells to die.• Reduces over expression of proteins.• Reduces cell proliferation and division.• Reduces risks of tumour and cancer.

Drug Therapies

Quazoo. Farnesyltransferase [Internet]. 2014 [cited 6 December 2014]. Available from: http://www.quazoo.com/q/Farnesyltransferase

R

T

K

R

T

K

Ras Pathway

SHC

GDP

GTP CD-GEGIIGAP

GTP

Elk1

c-FosATF2

c-Jun

Actin

Cytosk

elet

on

PP P

P

P

P

Stress Fibers and Focal AdhesionsStress Fibers and Focal Adhesions

GeneExpression

GeneExpression

PLDPathway

PLDPathway

PMAPMA

Growth FactorsGrowth FactorsIncreased T Cell

AdhesionIncreased T Cell

Adhesion

IntegrinsIntegrins

β1β1

β2β2 β2β2β1β1β1β1

SOS

p120-GAP

p190-B

Rho

PI3KPLC-ε

Rap1A

PLD RalBP1

PAKs

ERKs

ERKs

JNKK

JNKJNK

MEKK1

CDC42

Rac

MEKs

RafRalGDS

Ral

GRB2

TC

R

TC

R

AntigenAntigen

LckGEF

Ras Ras

2009ProteinLounge.com 2009ProteinLounge.comC

Thank You!Any Questions?

Sabiosciences.com. Pathway Central: Ras Pathway [Internet]. 2014 [cited 7 December 2014]. Available from: http://www.sabiosciences.com/pathway.php?sn=Ras_Pathway