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Gene Transcription

Gene Transcription. S. Growth Factors. +. Priming. G 1. G 0. G 2. Cell Cycle. M. Growth Factors & Cell Cycle. Receptors. ATP. ATP. TK. TK. +. EGFR Function in Normal Cell. Gene Transcription Cell Cycle Progression. Antiapoptosis. Cell Proliferation. Angiogenesis. TK. TK.

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Gene Transcription

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  1. GeneTranscription S Growth Factors + Priming G1 G0 G2 Cell Cycle M Growth Factors & Cell Cycle Receptors

  2. ATP ATP TK TK + EGFR Function in Normal Cell Gene Transcription Cell Cycle Progression Antiapoptosis Cell Proliferation Angiogenesis

  3. TK TK PTEN EGFR signal transduction in tumour cells PI3-K GRB2 pY pY SOS pY RAS RAF STAT3 AKT MEK Gene transcription MAPK G1 M S Survival(anti-apoptosis) Proliferation/maturation G2 Chemotherapy /radiotherapyresistance Metastasis Angiogenesis

  4. Mutation Consequence of proliferation of EGFR receptors Normal Cell Cancerous Cell Up Regulation

  5. ATP TK TK TK TK - - - - Strategies to inhibit EGFR signaling Anti-ligand mAbs EGFR tyrosine kinase inhibitors Immune effector cell BispecificAbs Anti-EGFR mAbs

  6. The PDGF-Receptor tyrosine kinase can bind several SH2-domain containing proteins simultaneously. { Ligand Binding Grb2 716Tyr-P PI,3 kinase 740Tyr-P { GAP 763Tyr-P Shc/Src 771Tyr-P Kinase Domain Shp2 1009Tyr-P 1021Tyr-P STAT 1043Tyr-P PLC-g

  7. Cytokines, Cell Stress Rac, Cdc42 PAK MEKK1 JNKK/SEK JNK The MAP Kinase (Extracellular-Related Kinase ERK) Cascade Mitogens, Growth Factors Ras GTPase MAP4K RAF } MAPKKK MAP3K MAP2K MAPKK/MEK1 MAPK MAPK Cytosol Transcriptional Regulation Nucleus

  8. Raf

  9. Background Information What is PDGF? • It is also known as platelet-derived growth factor. • There are four types of ligands: PDGFA, B, C, and D. • PDGF ligands are homodimers.

  10. If there are PDGF, there must be PDGFRs • Three types of receptors: PDGFR alpha alpha, alpha beta, and beta beta.

  11. PDGFRB’s Functions in Cellular Level • Receptor tyrosine kinase. • Ligand binding-> dimerization-> autophosphorylation. • Activates the Ras-MAPK, PI3K, & phospholipase C gamma pathways.

  12. PDGFR Activation Pathways Hoch & Soriano (2003) Development 130:4772

  13. What does PDGFRB do for the organism? • PDGFR + PDGF regulate development of vascular smooth muscle cells • Mice lacking PDGF or PDGFR die perinatally with extensive hemorrhaging.

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