The Tie2 RTK: Regulation and downstream signaling.

摘要

Tie2 is a receptor tyrosine kinase (RTK) involved in numerous aspects of both normal and pathological angiogenesis. Proper functioning of this receptor is essential for normal development of the vasculature in the embryo as well as vessel maintenance and at sites of active angiogenesis in the adult. A growing list of pathological states has been attributed to a disruption of the angiogenic 'balance' including psoriasis, arthritis, atherosclerosis and diabetic retinopathy. Elucidating the molecular mechanisms behind this important biological process will provide insight into the various molecules involved as well as provide potential targets for novel angiogenic therapies.;As well, we examined potential Tie2 downstream binding partners, specifically the novel Grb7 family of proteins. This work describes for the first time tyrosine phosphorylation of Grb14, an adaptor molecule previously shown to bind Tie2 in vitro. Moreover, our data suggests a role for this adaptor in Tie2 signal transduction involving two tyrosine residues in the receptor C-terminal tail; Y1100 and Y1106.;These studies provide important insight into both signal transduction downstream of Tie2 as well as help us understand some of the molecular mechanisms behind the intrinsic ability of this RTK to regulate its own activity.;In an attempt to better understand the signaling pathways downstream of the Tie2 receptor we have studied tyrosine residues on the receptor believed to play an important role in Tie2 function. Of these, we have identified Y1111 as a negative regulatory site on Tie2. Mutation of this site affects receptor phosphorylation and kinase activity. Furthermore, protease digestion studies indicate that mutation of Y1111 may alter receptor conformation and potentially relieve negative inhibition imparted by the C-tail of Tie2.