Paul Van Slyke:
Attenuation of EGFR-Dependent MAPK
Dok-R was cloned as a major phosphorylation substrate of the endothelial cell specific receptor tyrosine kinase, Tek/Tie2. Dok-R was the second in a family of three docking molecules to be identified which include p62dok, Dok-R/p56dok-2/FRIP and DOKL/dok-3. These docking molecules have been shown to bind several identical proteins, suggesting that they may play similar and/or redundant roles in cell signaling.
Careful observation has revealed that all of the docking molecules down-regulate cellular proliferation. It is currently believed that they accomplish this via attenuation of mitogen-activated protein (MAP) kinase activity, although the mechanism by which this occurs is still unknown.
Research conducted in our laboratory indicates that Dok-R is capable of associating with, and negatively regulating Src. Evidence will be presented to suggest that it is Dok-R's ability to negatively regulate Src that ultimately leads to MAP kinase attenuation.
Recently we have become interested in the role Dok-R may be playing in mediating vascular permeability. Vascular permeability is an important component of several pathologies including cerebral ischemia, tissue trauma, infection, rheumatoid arthritis and asthma, and as such, the mechanisms underlying this phenomenon and those mechanisms that naturally antagonize it are of significant clinical relevance.
While vascular endothelial growth factor (VEGF) is a potent endothelial cell mitogen it was originally described for its role in promoting vascular permeability. Mouse molecular genetic work has demonstrated an absolute requirement for Src family kinase members Src and Yes in these events. Although mechanisms underlying VEGF-mediated vascular permeability are becoming increasingly clear, there is still very little known about natural anti-permeability regulation.
A role for angiopoietin-1 in counteracting inflammation and VEGF-induced vascular permeability has been described by several groups. We are currently investigating the possibility that Dok-R, by virtue of its ability to negatively regulate Src, may mediate vascular permeability downstream of Tek/Tie2 receptor activation. Preliminary evidence as well as rationale for this hypothesis will be presented.
