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Vol. 9, Issue 8, 2157-2171, August 1998
and
*McArdle Laboratory for Cancer Research and Laboratory of Genetics
University of Wisconsin Medical School, Madison, Wisconsin 53706;
§Biology Department, University of Utah, Salt Lake City,
Utah 84112; and
Drosophila Enabled (Ena) was initially
identified as a dominant genetic suppressor of mutations in the Abelson
tyrosine kinase and, more recently, as a member of the Ena/human
vasodilator-stimulated phosphoprotein (VASP) family of proteins. We
have used genetic, biochemical, and cell biological approaches to
demonstrate the functional relationship between Ena and human VASP. In
addition, we have defined the roles of Ena domains identified as
essential for its activity in vivo. We have demonstrated that VASP
rescues the embryonic lethality associated with loss of Ena function in Drosophila and have shown that Ena, like VASP, is
associated with actin filaments and focal adhesions when expressed in
cultured cells. To define sequences that are central to Ena function,
we have characterized the molecular lesions present in two lethal ena mutant alleles that affected the Ena/VASP homology
domain 1 (EVH1) and EVH2. A missense mutation that resulted in an amino acid substitution in the EVH1 domain eliminated in vitro binding of Ena
to the cytoskeletal protein zyxin, a previously reported binding
partner of VASP. A nonsense mutation that resulted in a C-terminally
truncated Ena protein lacking the EVH2 domain failed to form multimeric
complexes and exhibited reduced binding to zyxin and the Abelson Src
homology 3 domain. Our analysis demonstrates that Ena and VASP
are functionally homologous and defines the conserved EVH1 and EVH2
domains as central to the physiological activity of Ena.
Medizinische Universitätsklinik,
Institut fur Klinische Biochemie und Pathobiochemie, D-97080
Würzburg, Germany
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