![About RAS…
By Irsalan Asif and Amy Bunch
Ras Pathway
GDP
GTP CD-GEGII
GA
P
GTP
Elk1
c-Fos
ATF2
c-Jun
P
P P
P
P
P
Stress Fibers and
Focal Adhesions
Gene
Expression
PLD
Pathway
PMA
Growth Factors
SO
S
p120-
GAP
p190-B
Rho
PI3KPLC-ε
Rap1
A
PLD RalBP1
PAKs
ERKs
ERKs
JNKK
JNK
JNK
MEKK1
CDC42
Rac
MEKs
Raf
RalGDS
Ral
GRB2
GE
F
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](https://image.slidesharecdn.com/raspresentationcomplete-150301124637-conversion-gate01/85/Ras-presentation-complete-1-320.jpg)
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Ras presentation complete
- 1. About RAS… By Irsalan Asif and Amy Bunch Ras Pathway GDP GTP CD-GEGII GA P GTP Elk1 c-Fos ATF2 c-Jun P P P P P P Stress Fibers and Focal Adhesions Gene Expression PLD Pathway PMA Growth Factors SO S p120- GAP p190-B Rho PI3KPLC-ε Rap1 A PLD RalBP1 PAKs ERKs ERKs JNKK JNK JNK MEKK1 CDC42 Rac MEKs Raf RalGDS Ral GRB2 GE F 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
- 2. Introduction Allows 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
- 3. 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.
- 4. 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
- 5. PI3K Active RAS CAAX extracellular intracellular 1. Activates p110 PI3K 2. Generates PI(4,5)P2 and PI(3,4,5)P3 messengers 3. These act as docking sites for serine-threonine kinases AKT or PKB 4. 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
- 6. Regulation of Ras NONf1 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.
- 7. 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
- 8. Ras Pathway GDP GTP CD-GEGII GA P GTP Elk1 c-Fos ATF2 c-Jun P P P P P P Stress Fibers and Focal Adhesions Gene Expression PLD Pathway PMA Growth Factors SO S p120- GAP p190-B Rho PI3KPLC-ε Rap1 A PLD RalBP1 PAKs ERKs ERKs JNKK JNK JNK MEKK1 CDC42 Rac MEKs Raf RalGDS Ral GRB2 GE F Ras Ras 2009 ProteinLounge.com C 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
Editor's Notes
- It remains anchored in the cell membrane for activation by CAAX It gets switched on by extracellular and intracellular signals inducing phosphorylation of receptor tyrosine kinase. Causing an adaptor protein to recruit Sos – which will phosphorylate the inactive RAS (GDP bound) to active RAS (GTP bound) This can now communicate (transducts information) with cellular components further down the signalling cascade.
- The peptide chain is presented as a ribbon β-strands are in gold, α-helices are red-coloured. Nucleotides are presented as bright yellow stick models magnesium ions as green spheres. Phosphate-binding P-loops are depicted in blue. The two switch regions of RAS molecule undergo spatial rearrangements upon GTP hydrolysis (SW I and SW II) are magenta coloured.
- Signal molecule binds a Receptor Tyrosine Kinase which self phosphorylates leading to Grb-2 and Sos becoming recruited. Sos is a GEF which initiates Ras by stimulating it to exchange GDP for GTP. Raf binds to the effector region of Ras-GTP and translocates to the plasma membrane. Ras tethered to the membrane by the CAAX box/HVR and Raf activated and phosphorylated. Raf then in turn activates MEK and MEK activates extracellular signal- regulated kinases ERK1/2
- GRB2 activates Sos which then activates Ras, similar to the MAPK pathway however Ras then activates p110 PI3K. This can be through a scaffold complex which involves Ras, GRB2, Sos which brings the activators in closer proximity. This then generates a second messenger protein PIP3 from PIP2 and this second messenger can activate a serine/threonine kinase which can be AKT or PKB. Target protein can promote cell growth and cell survival by inhibiting proapoptotic protein BAD
- Nitric oxide is a prevalent gas in the body and a stable free radical, hydrophobic in nature and extremely small in size. Can affect Ras as it contains a redox-sensitive NKCD motif, which can initiate a reaction with Ras. Lader treated cells with NO and found a higher percentage of Ras-GTP in the cell. NO induced signal transduction pathways downstream of Ras e.g. leading to stimulation of MAPK Another experiment showed NO- induced activation of Ras leading to PI3K and Raf recruitment. Nitric oxide is a prevalent gas in the body and a stable free radical, hydrophobic in nature and extremely small in size. Can affect Ras as it contains a redox-sensitive NKCD motif, which can initiate a reaction with Ras. Lader treated cells with NO and found a higher percentage of Ras-GTP in the cell. NO induced signal transduction pathways downstream of Ras e.g. leading to stimulation of MAPK Another experiment showed NO- induced activation of Ras leading to PI3K and Raf recruitment.