BIOL 4610 1st Edition Lecture 17Outline of Current Lecture1. Example of an RTK is the EGF receptor2. HER2 amplification in breast cancer3. The Ras/MAP kinase pathway4. RTKs and cytokine receptors linked to Ras by adapter proteins-GRB2 and Sos5. Transcription factors controlled by MAP kinase include c-fos and c-junCurrent Lecture1. Example of an RTK is the EGF receptor - the HER family – (human epidermal growth factor receptor)In humans, have 4 different isoforms of EGF receptor. Just called 1 2 3, 4. All bind to the epidermal growth factor signal. HER 1- dimerizes and binds to another HER 1 (homodimers)Heterodimers (HER 1 and HER 2)HER 3 has no activation Lip (doesn’t act as a kinase) so must bind to another HER with an activekinase domain to phosphorylate. HER 2 has no ligan binding; it’s in a pre-activated state so loops always extended; don’t need a signal so it’s constantly being told to divide divide divide. So cells deal with this by receptors only being expressed at a given time. 2. HER2 amplification in breast cancer and median survival rateHER 2- normally expressed at very low levels and in tissue-specific manner. (Ex. Breast tissue)Amplification- more copies in chromosome, so it makes too many proteinsThese notes represent a detailed interpretation of the professor’s lecture. GradeBuddy is best used as a supplement to your own notes, not as a substitute.Epidemiological study Data shows that since HER 2 exists in active state, it doesn’t need a signal and constantly divides. HER 2 has no ligand binding domainHerceptin- antibody that targets the extracellular domain (loop) and prevents dimerization. This is the first drug you would get if you had HER 2 breast cancer. 16.2. The Ras/MAP kinase pathwayRas: monomeric GTPase - Bound to GDP in inactive state- Bound to GTP in active state- Require guanine exchange factor GEF in order to remove the GDP and allow GTP to bind.- Ras’s GEF is Sos.- Ras’s GTPase activity is very slow (~1 minute to cleave off GTP à GDP)- Needs GAP (GTPase Acceleration Protein) - Raf is one of Ras’s GAP- Ras is one of most frequently mutated proteinsRTKs and cytokine receptors linked to Ras by adapter proteins-GRB2 and SosEGF receptor - Bound by ligand- Dimerized- P tyrosines- GRB2 has 2 domains:1. SH2 Domain- bind to phoshorylated tyrosines2. SH3 domain- bind to areas rich in prolinesSos: 1. Proline rich domain (bind with GRB2)2. GEF - activityStarts a cascade of protein kinases- active RasRas recruits a protein called Raf -binds to active Ras and phosphorylates itself-Raf acts as the GAP proteinReleases phosphorylated Raf from Ras-get an active kinase in the cytoplasmNow we can start moving away from membrane and get to nucleusTranscription factors controlled by MAP kinase include c-fos and c-junMAP kinase can act as a transcription factor when phosphorylated Also phosphorylates P-90 à comes into nucleus and phosphorylates SRFFinal proteins made (target proteins that get transcribed at the end of the EGF-Ras-MAP kinase pathway)This helps start S phase of the cell
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