Section 3 Quantitiative Description of Intracellular Signaling The growth factor signaling pathway or mitogen-activated

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Section 3 Quantitiative Description of Intracellular Signaling The growth factor signaling pathway or mitogen-activated protein kinase (MAP kinase) is a cascade of receptor tyrosine kinases or RTKs which are found in eukaryotic cells. This signaling array drives a signal from the extracellular space to the nucleus of the cell. The activation of extracellular signal-regulated kinase (ERK) is a fundamental process in the formation and differentiation of cells. Interestingly the function of the ERK pathway was discovered from oncogenic studies of Ras proteins (guanine nucleotide binding proteins) in rats. In general the signaling cascade is initiated by the extracellular binding of a ligand to the growth factor which typically dimgrizes and becomes phosphorylated. This then binds with proteins such as GRB2 (containing SH2) which binds to the SOS exchange factor, activating the SOS. This activated SOS stimulates the change from GDP to GTP which allows the binding of the Ras protein and GTP. Activated Ras triggers the activation of the Raf protein-serine/threonine kinase which phosphorylates the MAP/ERK kinase (MEK) MEK is then activated. The activation of MEK induces the activation of the ERK. Finally the ERK pathway leads to the phosphorylation of other proteins and transcription factors in the cell completing the cascade. The schematic description of the Heregulin (HRG) activated MAPK signaling cascade. Certain aspects of the cascade are well understood with supporting literature such as the MEK, ERK phosphorylation pathways, Ras to Raf pathways (the activation of Raf by unknown enzyme could use additional understanding) and adapter proteins. Particularly, it is well understood what the key players in the process
The schematic description of the Heregulin (HRG) activated MAPK signaling cascade. Certain aspects of the cascade are well understood with supporting literature such as the MEK, ERK phosphorylation pathways, Ras to Raf pathways (the activation of Raf by unknown enzyme could use additional understanding) and adapter proteins. Particularly, it is well understood what the key players in the process are, however the exact mechanics are sometimes poorly understood. In particular much approximation is necessary for the time dynamic of the model as well as the order of many of the kinetic parameters, (see Table 1). Additionally inhibitory negative feedback through binding protein and phosphatases with unknown catalysts further demonstrate a lack of complete understanding of this complicated process. Thus it is acceptable to neglect them where necessary. In this section you will describe the equations summarizing the reactions given below then using the initial concentrations given in Table 2 to determine the response of the cell to a given ligand concentration.
HRG 11, K11 Lin RasGDP RasGIP BERG R-HRG VIZ, K12 Membrane. extracellular 2 M2n 2013. K13 R HRG2 V4, K4 3 Raf 1 Ral RP Internalization 114, 114 She 1515 115, K15 17,17 R-Shc MEK VIO, K10 МЕКР MEKPP 16 k16, K16 KLB KLS R-Shp Shir PP2A GS 17T Membrane, intracellular R-SHOS 19, K19 121, 121 19 8 Cytosol RP ERK ERKP ERKPP SHGS 120.20 22,22 Mass action Forwarding Mich. Ment. constant Mich. Ment. variable MP3
Table 1. Kinetic parameters kı= 1.2 e 3 kin=7.6 e1 kz=0.01 k2n=0.1 k3= 1.0 k3n=0.01 V = 62.5 K4=50 k5= 0.1 k5n=1 k6= 20 kon=5 k = 60 kZn=546 kg= 2040 k8n=157000 k9= 40.8 k9n=0 V10=0.0154 K10=340 ku= 0.222 K11=0.181 V12=0.289 K12=0.0571 k13= 1.53 K13=11.7 K14= 6.73 e3 K1458.07 kis= 3.5 K15=317 k16= 0.058 K16=2200
k17= 2.9 K18= 0.058 K19= 9.5 K20= 0.3 K21= 16 K22= 0.27 K23= 1.0 e 3 K17=317 K18=6 K19=1.46 es K20=160 K21=1.46 es K22=60 K23=0 Table 2. Initial Concentrations (nM) R= 80 ShC=1000 GS=10 RasGDP=120 Raf=100 MEK=120 ERK=1000 E=7 MKP3=2.4 PP2A=11.4
1. (30 points) Describe the quantitative equations explaining Raf activation by the Growth Factor (GF) binding 2. (30 points) Determine the Raf response of the cell to HRG concentrations given below and plot the relation in a scatter plot using excel. HRG System Response (Raf) 1 nM 2 nM 4 nM 5 nM 10 nM