Ras presentation complete
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About RAS… By Irsalan Asif and Amy Bun R T K R T K Ras Pathway SHC GDP GTP CD- GEGII GAP GTP Elk1 c-Fos ATF2 c-Jun Actin Cytoskeleton P P P P P P Stress Fibers and Focal Adhesions Gene Expression PLD Pathway PMA Growth Factors Increased T Cell Adhesion Integrin s β1 β2 β2 β1 β1 SOS p120 - GAP p190-B Rho PI3K PLC-ε Rap1A PLD RalBP1 PAKs ERKs ERKs JNKK JNK JNK MEKK1 CDC42 Rac MEKs Raf RalGDS Ral GRB2 T C R Antigen Lck GEF Ras Ras 2009 ProteinLounge.com C Sabiosciences.com. Pathway Central: Ras Pathway [Internet]. 2014 [cited 7 December 2014]. Available from: http://www.sabiosciences.com/pathway.php? sn=Ras_Pathway
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Transcript of Ras presentation complete
About RAS…By Irsalan Asif and Amy Bunch
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
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
