Tes, a Specific Mena Interacting Partner, Breaks the Rules for EVH1 Binding

Cell Motility Laboratory, Cancer Research UK, London Research Institute, 44 Lincoln's Inn Fields, London, WC2A 3PX, UK.
Molecular Cell (Impact Factor: 14.46). 01/2008; 28(6):1071-82. DOI: 10.1016/j.molcel.2007.10.033
Source: PubMed

ABSTRACT The intracellular targeting of Ena/VASP family members is achieved via the interaction of their EVH1 domain with FPPPP sequence motifs found in a variety of cytoskeletal proteins, including lamellipodin, vinculin, and zyxin. Here we show that the LIM3 domain of Tes, which lacks the FPPPP motif, binds to the EVH1 domain of Mena, but not to those of VASP or Evl. The structure of the LIM3:EVH1 complex reveals that Tes occludes the FPPPP-binding site and competes with FPPPP-containing proteins for EVH1 binding. Structure-based gain-of-function experiments define the molecular basis for the specificity of the Tes-Mena interaction. Consistent with in vitro observations, the LIM3 domain displaces Mena, but not VASP, from the leading edge and focal adhesions. It also regulates cell migration through a Mena-dependent mechanism. Our observations identify Tes as an atypical EVH1 binding partner and a regulator specific to a single Ena/VASP family member.

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Available from: David Briggs, Jul 17, 2015
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    • "One molecular explanation for this could be the sustained expression of CDKN1C and TES within the mesodermal progenitors. CDKN1C and TES are known regulators of cell cycle and cell motility, respectively (Pateras et al. 2006; Boeda et al. 2007), and we demonstrated that knockdown of TES in M-iG7 cells reduces their motility in vitro (Supplemental Fig. 4C). In NS-like cells derived from the GiPSCs, expression of CDKN1C and TES were not sustained despite removal of DNA hypermethylation. "
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    • "The INV exon is inserted just after the EVH1 domain, which is primarily responsible for the subcellular localization of Ena/VASP proteins and interactions with several signaling proteins such as Lamellipodin (Gertler et al., 1996; Urbanelli et al., 2006; Pula and Krause, 2008). It is therefore possible that the INV exon might influence the function of Mena INV by regulating its EVH1-mediated interactions (Niebuhr et al., 1997; Boeda et al., 2007). The 11a exon is inserted within the EVH2 domain between the F-actin binding motif and the coiled-coil tetramerization site. "
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