Sandbox Reserved 1490: Difference between revisions
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TIE2 maintains the vascular integrity of mature vessels by enhancing endothelial barrier function and inhibiting apoptosis of endothelial cells.<ref>PMID:18425120</ref> | TIE2 maintains the vascular integrity of mature vessels by enhancing endothelial barrier function and inhibiting apoptosis of endothelial cells.<ref>PMID:18425120</ref> | ||
ANGPT1 is a TIE2 agonist : in vitro, it binds to TIE2 and induces its activation via tyrosine phosphorylation. In vivo, it was proven that inactivation of ANGPT1 or over expression of ANGPT2 produce similar effects.<ref name="Mechanistic effects of autophosphorylation">PMID: | ANGPT1 is a TIE2 agonist : in vitro, it binds to TIE2 and induces its activation via tyrosine phosphorylation. In vivo, it was proven that inactivation of ANGPT1 or over expression of ANGPT2 produce similar effects.<ref name="Mechanistic effects of autophosphorylation">PMID: 19223473</ref> | ||
ANGPT2 is a competitive antagonist of TIE2 or a partial agonist of TIE2 depending on the context. In stressed ECs, one recent report suggests that ANGPT2 may activate TIE2 signaling in the absence of ANGPT1 and in high concentrations. | ANGPT2 is a competitive antagonist of TIE2 or a partial agonist of TIE2 depending on the context. In stressed ECs, one recent report suggests that ANGPT2 may activate TIE2 signaling in the absence of ANGPT1 and in high concentrations. | ||
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===• Signal transduction and kinase activity=== | ===• Signal transduction and kinase activity=== | ||
Receptor tyrosine kinases are transmembrane proteins with a [[2gy5|ligand-binding extracellular domain]], a single membrane-spanning domain, a juxtamembrane region, a catalytic domain, and a C-terminal tail.<ref>PMID:11513602</ref> | Receptor tyrosine kinases are transmembrane proteins with a [[2gy5|ligand-binding extracellular domain]], a single membrane-spanning domain, a juxtamembrane region, a catalytic domain, and a C-terminal tail.<ref name="Mechanistic effects of autophosphorylation">PMID: 11513602</ref> In cell culture, ANGPT1 induces phosphorylation of TIE2 and stimulates endothelial cell migration and survival. | ||
The activation of the receptor is due to a ligand-induced dimerization : the extracellular receptor domain dimerization brings the cytosolic kinase domains next to each other for intermolecular autophosphorylation. The latter occurs when one subunit of the dimeric receptor phosphorylates tyrosine residues on the other subunit. It happens in a sequential manner : Tyr-992 in the kinase activation loop is phosphorylated first, followed by autophosphorylation at Tyr-1108 and at additional tyrosine residues. Autophosphorylation also has multiple functions including recruitment of downstream signaling molecules.<ref | The activation of the receptor is due to a ligand-induced dimerization : the extracellular receptor domain dimerization brings the cytosolic kinase domains next to each other for intermolecular autophosphorylation. The latter occurs when one subunit of the dimeric receptor phosphorylates tyrosine residues on the other subunit. It happens in a sequential manner : Tyr-992 in the kinase activation loop is phosphorylated first, followed by autophosphorylation at Tyr-1108 and at additional tyrosine residues. Autophosphorylation also has multiple functions including recruitment of downstream signaling molecules.<ref name="Mechanistic effects of autophosphorylation" /> | ||
Looking more closely at the TIE2 intracellular domain, 1106 is found at the base of a loop formed between the C-terminus tail and the C-terminus lobe of the kinase. The OH group of Tyr-1106 is thus directly into the solvent and accessible to phosphorylation. However, Tyr-1100 is not solvent exposed : thereby implying that the carboxy-terminal tail must undergo a conformational change upon activation of the receptor to expose this tyrosine residue for phosphorylation.<ref>PMID:12665569</ref> | Looking more closely at the TIE2 intracellular domain, 1106 is found at the base of a loop formed between the C-terminus tail and the C-terminus lobe of the kinase. The OH group of Tyr-1106 is thus directly into the solvent and accessible to phosphorylation. However, Tyr-1100 is not solvent exposed : thereby implying that the carboxy-terminal tail must undergo a conformational change upon activation of the receptor to expose this tyrosine residue for phosphorylation.<ref>PMID:12665569</ref> | ||
