Figure 6 | Tie2 signal transduction, showing the known binding partners for Tie2.   The p85 regulatory subunit of phosphatidylinositol-3-OH kinase (PI(3)K) associates with the phosphorylated Tie2 receptor, presumably through tyrosine residue 1100, resulting in stimulation of PI(3)K. Subsequent activation of the serine/threonine kinase Akt correlates with an increase in cell survival, although the exact mechanism by which this occurs remains to be determined. Alternatively, PI(3)K activity is coincident with focal adhesion kinase (FAK) activation and cell migration. Grb7 and the protein tyrosine phosphatase Shp2 might also use this pathway to potentiate cell migration and they seem to be recruited to the receptor through tyrosine residues 1100 and 1111, respectively^{55, 56}. The effects of Dok-R (docking protein) recruitment to Tie2 and its downregulation of mitogen-activated protein kinase (MAPK) and cell proliferation are inferred from our studies on the epidermal growth factor receptor¹⁰⁷, and we have shown that Dok-R can enhance p21-activated (Pak)-dependent cell migration in response to angiopoietin-1 through its association with Nck. The significance of Grb2 and Grb14 binding to Tie2, as well as binding of the Ras GTPase-activating protein RasGAP to Dok-R, are now under investigation. The binding sites for Grb14 and Dok-R are from our unpublished results (N.J. and D.J.D.). Solid arrows indicate pathways that are known to exist downstream of Tie2 and dashed arrows indicate links that have been demonstrated using other receptor signalling models. The vascular endothelial protein tyrosine phosphatase (VE-PTP) is illustrated at the cell membrane and HCPTPA (human cellular protein tyrosine phosphatase A) has been omitted from this schematic. (NOS, nitric oxide synthase.)

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