PubMed Journals: J Biol Chem
Source: PMID: 10521483
⇦ ⇨ J Biol Chem. 1999 Oct 22;274(43):30896-905.
Identification of Tek/Tie2 binding partners.
Binding to a multifunctional docking site
mediates cell survival and migration.
Jones N(1), Master Z, Jones J, Bouchard
D, Gunji Y, Sasaki H, Daly R, Alitalo K,
(1) Division of Cancer Biology Research,
Sunnybrook and Women's College Health Sciences
Centre, University of Toronto, Toronto,
Ontario M4N 3M5.
The Tek/Tie2 receptor tyrosine kinase plays
a pivotal role in vascular and hematopoietic
development. To study the signal transduction
pathways that are mediated by this receptor,
we have used the yeast two-hybrid system
to identify signaling molecules that associate
with the phosphorylated Tek receptor. Using
this approach, we demonstrate that five
molecules, Grb2, Grb7, Grb14, Shp2, and
the p85 subunit of phosphatidylinositol
3-kinase can interact with Tek in a
phosphotyrosine-dependent manner through
their SH2 domains. Mapping of the binding
sites of these molecules on Tek reveals
the presence of a multisubstrate docking
site in the carboxyl tail of Tek (Tyr(1100)).
Mutation of this site abrogates binding
of Grb2 and Grb7 to Tek in vivo, and this
site is required for tyrosine phosphorylation
of Grb7 and p85 in vivo. Furthermore, stimulation
of Tek-expressing cells with Angiopoietin-1
results in phosphorylation of both Tek and
p85 and in activation of endothelial cell
migration and survival pathways that are
dependent in part on phosphatidylinositol
3-kinase. Taken together, these results
demonstrate that Angiopoietin-1-induced
signaling from the Tek receptor is mediated
by a multifunctional docking site that is
responsible for activation of both cell
migration and cell survival pathways.
PMID: 10521483 [Indexed for MEDLINE]