Growth factors: Difference between revisions
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The <scene name='80/801744/Cv/4'>kinase domain of M-CSF receptor interacts with a drug-designed inhibitor</scene> via the conserved kinase DFG motif (colored in salmon) and its gatekeeper threonine residue (colored in magenta)<ref>PMID:23493555</ref>. | The <scene name='80/801744/Cv/4'>kinase domain of M-CSF receptor interacts with a drug-designed inhibitor</scene> via the conserved kinase DFG motif (colored in salmon) and its gatekeeper threonine residue (colored in magenta)<ref>PMID:23493555</ref>. | ||
*[[Epidermal growth factor]] and [[Epidermal Growth Factor Receptor]] (EGFR). EGFR belongs to [[Receptor tyrosine kinases]], class I. | *[[Epidermal growth factor]] and [[Epidermal Growth Factor Receptor]] (EGFR). EGFR belongs to [[Receptor tyrosine kinases]], class I. | ||
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<scene name='Vascular_Endothelial_Growth_Factor/Vegf-a_opening/1'>VEGF-A</scene> is a homodimer composed of two 23 kDa subunits. VEGF-A exists in a number of different isoforms following alternative splicing of its precursor mRNA <ref>PMID: 11181169</ref>. In humans, 6 variants have been found: VEGF-A-121, VEGF-A-145, VEGF-A-165, VEGF-A-183, VEGF-A-189, and VEGF-A-206, with VEGF-A-165 the most abundantly expressed. All VEGF-A isoforms bind to VEGFR-1 and -2. | <scene name='Vascular_Endothelial_Growth_Factor/Vegf-a_opening/1'>VEGF-A</scene> is a homodimer composed of two 23 kDa subunits. VEGF-A exists in a number of different isoforms following alternative splicing of its precursor mRNA <ref>PMID: 11181169</ref>. In humans, 6 variants have been found: VEGF-A-121, VEGF-A-145, VEGF-A-165, VEGF-A-183, VEGF-A-189, and VEGF-A-206, with VEGF-A-165 the most abundantly expressed. All VEGF-A isoforms bind to VEGFR-1 and -2. | ||
The amino acids determined to be <scene name='Vascular_Endothelial_Growth_Factor/Vegf-a_binding_to_vegfr1/2'>critical to binding to VEGFR-1</scene> are D63, L66, and E67. VEGF-A binding by VEGFR-1 leads to cellular proliferation, migration, and increased cellular permeability resulting in vasculogenesis and angiogenesis. Those residues <scene name='Vascular_Endothelial_Growth_Factor/Vegf-a_binding_to_vegfr2/2'>critical to binding to VEGFR-2</scene> are I43, I46, Q79, I83, K84 and P85.<ref>pmid:9207067</ref> Binding of VEGF-A to VEGFR-2 results in similar Vasculogenesis and angiogenesis, but also lymphangiogenesis in embryos. The remainder of the <scene name='Vascular_Endothelial_Growth_Factor/Vegf-a_full_binding_site/1'>binding pocket </scene> is formed by D34, S50, E64, and F36. It is upon binding of VEGFR by VEGF that the subsequent signal cascade is initiated leading to angiogenesis, etc.<ref>pmid:8621427</ref> | The amino acids determined to be <scene name='Vascular_Endothelial_Growth_Factor/Vegf-a_binding_to_vegfr1/2'>critical to binding to VEGFR-1</scene> are D63, L66, and E67. VEGF-A binding by VEGFR-1 leads to cellular proliferation, migration, and increased cellular permeability resulting in vasculogenesis and angiogenesis. Those residues <scene name='Vascular_Endothelial_Growth_Factor/Vegf-a_binding_to_vegfr2/2'>critical to binding to VEGFR-2</scene> are I43, I46, Q79, I83, K84 and P85.<ref>pmid:9207067</ref> Binding of VEGF-A to VEGFR-2 results in similar Vasculogenesis and angiogenesis, but also lymphangiogenesis in embryos. The remainder of the <scene name='Vascular_Endothelial_Growth_Factor/Vegf-a_full_binding_site/1'>binding pocket </scene> is formed by D34, S50, E64, and F36. It is upon binding of VEGFR by VEGF that the subsequent signal cascade is initiated leading to angiogenesis, etc.<ref>pmid:8621427</ref> | ||
<scene name='Vascular_Endothelial_Growth_Factor/Vegf-e_opening/1'>VEGF-E</scene> consists of a homodimer that is covalently linked by two intermolecular disulfide bonds between <scene name='41/411433/Cys51-cys60/1'>Cys51 and Cys 60</scene>. | |||
Each monomer contains a central antiparallel beta sheet, with the canonical <scene name='41/411433/Knot_new/3'>cysteine knot </scene> found in other VEGFs. <ref>PMID:1396586</ref> The knot consists of an eight residue ring formed by the backbone of residues 57-61 and 102-104 and intramolecular disulfide bridges Cys57-Cys102 and Cys61-Cys104, and a third bridge, Cys26-Cys68, that passes perpendicularly through the ring. Each VEGF-E monomer contains an amino terminal alpha helix and three solvent accessible loop regions, L2, <scene name='41/411433/Vegf-e_l1_l3/3'>L1 and L3 </scene>. | |||
are able to form a complex hydrogen bond network as well as extensive hydrophobic contacts with VEGFR making these loops ideal receptor specificity determinants. Residues: P34, S36, T43, P50, R46, D63, E64, and E67 make up the <scene name='Vascular_Endothelial_Growth_Factor/Vegf-e_binding_site/1'>VEGF-E binding pocket </scene>and are critical for binding to VEGFR-2 as determined by alanine mutagenesis.<ref> PMID:16672228</ref> Further, the salt bridge between <scene name='41/411433/Vegf-e_salt_bridge/4'>R46 and E64 </scene> is believed to be the source of VEGF-E’s VEGFR-2 specificity by preventing binding to VEGFR-1. <ref>PMID:15272021</ref> | |||
[[Vascular Endothelial Growth Factor Receptor]]s (VEGFRs) are [[tyrosine kinase receptors]] responsible for binding with [[VEGF]] to initiate signal cascades that stimulate angiogenesis among other effects. The tyrosine kinase domain of VEGFR-2 is separated into 2 segments with a 70 amino acid long kinase insert region. Upon binding VEGFA and subsequent dimerization, VEGFR-2 is autophosphoryalted at the carboxy terminal tail and kinase insert region, 6 tyrosine residues of VEGFR2 are autophosphorylated. <scene name='41/411436/Cv/2'>Auto-phosphorylation of residues 1054 and 1059</scene> within the activation loop of VEGFR2 leads to increased kinase activity. <scene name='41/411436/Cv/4'>Anti-tumor inhibitor binding site</scene> ([[3c7q]]). | |||
See also [[Bevacizumab]]. | |||
*[[TGF-beta receptor|Transforming Growth Factor and its receptor]] | *[[TGF-beta receptor|Transforming Growth Factor and its receptor]] | ||