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VEGF Signaling – An overview
Presented by Prabhu T, Research scholar, Dept .of Biotechnology. Sahyadri science college, Shimoga
20th January,2013
1- Vasculogenesis - Angiogenesis - Arteriogenesis
VasculogenesisFormation of blood vessels by differentiation from (hem)angioblasts
Sprouting angiogenesisSprouting of cells from mature endothelial cells of the vessel wall
Arteriogenesisgrowth of large arteries from pre-existing small vessels/capillaries
LymphangiogenesisFormation of the lymphatic vasculature
Life time of endothelial cells:
months (lung, liver) to years (brain, muscle)
Slow repair and renewal of vascular wall
New vessel formation:
Embryo, growthIn uterus, during menstruation cycleWound repair
Sprouting towards chemotactic gradient: VEGF
Hypoxia - HIF - VEGFevery cell must be within 50 to 100 mm of a capillary
HIF: hypoxia inducible factorVEGF: vascular endothelial growth factor
VEGF/VEGFR:VEGF-A: initiation of vasculogenesisand 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 vesselsVEGF-D: lymphatic vessels
VEGFR-2: growth and permeabilityVEGFR-1: negative role , decoy receptor,
synergism with VEGFR-2 in tumor angiogenesis VEGFR-3: lymphatic vessels
VEGF/VEGFR family
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
Angiogenesis
Ras/MAP kinase pathway
VEGF VEGF
Grb-2 Adaptor: SH2- Domain
SOS is a Ras-GEF (guanine nucleotide exchange factor)
Ras: GTP-binding Protein (Oncogene detected in Rat Sarcoma)
SOS
Ras activates MAP-Kinase Pathway
1- MAPKKK2- MAPKK3- MAPK
MAPK: Mitogen-activated Kinase
(there are three MAP-Kinase cascades:MEK/ERKP38JNK)
Raf
MEK
ERK
f
The phosphorylated MAPK ERK is transported into the nucleusand phosphorylates the transcription factor TCF
ERK: extracellular signal regulated kinaseTCF: ternary complex factorSRF: serum response factorSRE: serum response element
(DNA binding sequence for TCF and SRF in promoter of different genes)
Genes forCell cycle/Proliferation,e.g. c-Fos,TCFSRF and Jun
PKC signaling pathway
PKB, PDK:(PDK: PI-dependent kinase)
Ser/Thr kinases
Akt/PI-3 Kinase Pathway and Survival
VEGF
Talin and Vinculin
Angiogenesis-dependent diseases
excessCancer
Infantile hemangiomas
Autoimmune diseases, chronic inflammatory diseases:Rheumatoid arthritisPsoriasis
Age-related macular degeneration
Atherosclerosis
Deficiency:Limb ischemiaMyocardial ischemia
References
Books:
B. Alberts et al., Molecular Biology of the Cell,5th Edition, Taylor and Francis Inc., 2007Pg. 1279-1283
Endothelial BiomedicineW. Aird, ed.Cambridge University Press, 2007
R.A. Weinberg, The Biology of Cancer, Garland Science, 2007Pg. 556-585
Tumor Angiogenesis - Basic mechanisms and Cancer Therapy, D. Marme, N. Fusenig, ed.Springer Verlag 2008
By,Prabhu T,20th January,2013