Functional analysis of a mutant form of the receptor tyrosine kinase Tie2 causing venous malformations.
Tie2 is expressed predominantly in endothelial cells and is required for blood vessel formation and maintenance. A missense mutation resulting in an R to W substitution in the kinase domain of Tie2 co-segregates with an autosomal dominantly inherited form of vascular dysmorphogenesis, venous malformation (VM). The mechanism by which this activating mutation leads to vessel dysmorphogenesis in VM is not known. Here we examined Tie2 activation status in VM and found activated receptor in lesional and non-lesional vessels. To gain insight into functional effects of VM mutant Tie2, wild-type and R849W mutant receptor were expressed in cultured human venous endothelial cells. Mutant Tie2 was constitutively phosphorylated in endothelial cells in vivo and caused a marked suppression of apoptosis. The anti-apoptotic kinase Akt was constitutively activated in cells expressing mutant receptor. Dominant-negative Akt inhibited the pro-survival activity of mutant Tie2. Migration of smooth muscle cells induced by conditioned medium from cells expressing mutant receptor was similar to that from cells expressing wild-type receptor. These data suggest that a primary effect of R849W Tie2 in VM is to allow survival of mural cell poor vessels via ligand-independent Tie2 activation of Akt and endothelial survival, rather than to directly induce formation of dysmorphogenic vessels.
Morris
Paul N
PN
Department of Cardiovascular Sciences, University of Leicester, RKCSB, P.O. Box 65, Leicester, LE2 7LX, UK.
Dunmore
Benjamin J
BJ
Tadros
Amir
A
Marchuk
Douglas A
DA
Darland
Diane C
DC
D'Amore
Patricia A
PA
Brindle
Nicholas P J
NP
D019943:Amino Acid Substitution; D017209:Apoptosis / Q000235:genetics / Q000502:physiology; D004730:Endothelium, Vascular / Q000502:physiology*; D006801:Humans; D017354:Point Mutation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D042787:Receptor, TIE-2 / Q000235:genetics* / Q000502:physiology; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D014680:Veins / Q000002:abnormalities*
D011518:Proto-Oncogene Proteins; D042787:Receptor, TIE-2; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt