Vegf signaling


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vegf signaling

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Vegf signaling

  1. 1. VEGF Signaling – An overview Presented by Prabhu T, Research scholar, Dept .of Biotechnology. Sahyadri science college, Shimoga 20th January,2013
  2. 2. 1- Vasculogenesis - Angiogenesis - Arteriogenesis Vasculogenesis Formation of blood vessels by differentiation from (hem)angioblasts Sprouting angiogenesis Sprouting of cells from mature endothelial cells of the vessel wall Arteriogenesis growth of large arteries from pre-existing small vessels/capillaries Lymphangiogenesis Formation of the lymphatic vasculature
  3. 3. Life time of endothelial cells: months (lung, liver) to years (brain, muscle) Slow repair and renewal of vascular wall New vessel formation: Embryo, growth In uterus, during menstruation cycle Wound repair
  4. 4. Sprouting towards chemotactic gradient: VEGF
  5. 5. Hypoxia - HIF - VEGF every cell must be within 50 to 100 m of a capillary HIF: hypoxia inducible factor VEGF: vascular endothelial growth factor
  6. 6. VEGF/VEGFR: VEGF-A: initiation of vasculogenesis and sprouting angiogenesis, Immature vessels, Vascular permeability factor, Haploid insufficiency in k.o. mice, PlGF: remodeling of adult vessels VEGF-B: heart vascularization VEGF-C: lymphatic vessels VEGF-D: lymphatic vessels VEGFR-2: growth and permeability VEGFR-1: negative role , decoy receptor, synergism with VEGFR-2 in tumor angiogenesis VEGFR-3: lymphatic vessels VEGF/VEGFR family
  7. 7. VEGF signaling pathways Ras/MAP kinase pathway – Gene expression and proliferation Akt/PI3K pathway – cell survival NOS pathway – vascularpermeability PKC pathway – cell proliferation and vascularpermeability FAK/Paxillin pathway – cytoskeletal rearrangement and cell migration A n g i o g e n e s i s
  8. 8. Ras/MAP kinase pathway VEGFVEGF
  9. 9. Grb-2 Adaptor: SH2- Domain SOS is a Ras-GEF (guanine nucleotide exchange factor) Ras: GTP-binding Protein (Oncogene detected in Rat Sarcoma) SOS
  10. 10. Ras activates MAP-Kinase Pathway 1- MAPKKK 2- MAPKK 3- MAPK MAPK: Mitogen-activated Kinase (there are three MAP-Kinase cascades: MEK/ERK P38 JNK) Raf MEK ERK f
  11. 11. The phosphorylated MAPK ERK is transported into the nucleus and phosphorylates the transcription factor TCF ERK: extracellular signal regulated kinase TCF: ternary complex factor SRF: serum response factor SRE: serum response element (DNA binding sequence for TCF and SRF in promoter of different genes) Genes for Cell cycle/ Proliferation, e.g. c-Fos,TCF SRF and Jun
  12. 12. PKC signaling pathway
  13. 13. PKB, PDK: (PDK: PI-dependent kinase) Ser/Thr kinases Akt/PI-3 Kinase Pathway and Survival VEGF
  14. 14. Talin and Vinculin
  15. 15. Angiogenesis-dependent diseases excess Cancer Infantile hemangiomas Autoimmune diseases, chronic inflammatory diseases: Rheumatoid arthritis Psoriasis Age-related macular degeneration Atherosclerosis Deficiency: Limb ischemia Myocardial ischemia
  16. 16. References Books: B. Alberts et al., Molecular Biology of the Cell, 5th Edition, Taylor and Francis Inc., 2007 Pg. 1279-1283 Endothelial Biomedicine W. Aird, ed. Cambridge University Press, 2007 R.A. Weinberg, The Biology of Cancer, Garland Science, 2007 Pg. 556-585 Tumor Angiogenesis - Basic mechanisms and Cancer Therapy, D. Marme, N. Fusenig, ed. Springer Verlag 2008 By, Prabhu T, 20th January,2013