title: Tie-1 receptor tyrosine kinase endodomain interaction with SHP2: potential signalling mechanisms and roles in angiogenesis.
abstract: The endothelial receptor tyrosine kinase plays an essential role in vascular development where it is thought to be required for vessel maturation and stabilization. The ligands responsible for activating Tie-1, its signalling pathways and specific cellular functions are however not known. As with some other receptor tyrosine kinases, Tie-1 is subject to extracellular proteolytic cleavage generating a membrane bound receptor fragment comprising the intracellular and transmembrane domains. Here we examine the signalling potential of this Tie-1 endodomain. We show that the Tie-1 endodomain has poor ability to induce tyrosine phosphorylation. However, on formation the endodomain physically associates with a number of tyrosine phosphorylated signalling intermediates including the tyrosine phosphatase and adaptor protein SHP2. The assembly of this multimolecular complex is consistent with the endodomain having a ligand-independent signalling role in the endothelial cell. The potential roles of ectodomain cleavage and cleavage activated signalling in regulating microvessel stability in angiogenesis, vessel remodelling and regression are considered.
authors.affiliation: University of Leicester Cardiovascular Research Institute, UK.
authors.forename: M B
authors.initials: MB
authors.lastname: Marron
authors.forename: D P
authors.initials: DP
authors.lastname: Hughes
authors.forename: M J
authors.initials: MJ
authors.lastname: McCarthy
authors.forename: E R
authors.initials: ER
authors.lastname: Beaumont
authors.forename: N P
authors.initials: NP
authors.lastname: Brindle
mesh_terms: D000818:Animals; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D018919:Neovascularization, Physiologic / Q000502:physiology*; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism*; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism / Q000502:physiology*; D042810:Receptor, TIE-1; D011956:Receptors, Cell Surface / Q000378:metabolism / Q000502:physiology*; D042764:Receptors, TIE; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D011956:Receptors, Cell Surface; D020794:Receptor Protein-Tyrosine Kinases; D042810:Receptor, TIE-1; D042764:Receptors, TIE; C516724:PTPN11 protein, human; C509249:PTPN6 protein, human; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases