Abi-1-bridged tyrosine phosphorylation of VASP by Abelson kinase impairs association of VASP to focal adhesions and regulates leukaemic cell adhesion

Maruoka, Masahiro; Sato, Mariko; Yuan, Yunfeng; Ichiba, Masayoshi; Fujii, Ryosuke; Ogawa, Teiichiro; Ishida-Kitagawa, Norihiro; Takeya, Tatsuo; Watanabe, Naoki

doi:10.1042/bj20110951

Cited by 37 publications

(49 citation statements)

References 60 publications

(116 reference statements)

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“…This region has previously been implicated in function, as mutation of the nearby Y39 altered the co-localization of and interaction between VASP and Zyxin. 23 …”

Section: Resultsmentioning

confidence: 99%

A Noncanonical Binding Site in the EVH1 Domain of Vasodilator-Stimulated Phosphoprotein Regulates Its Interactions with the Proline Rich Region of Zyxin

2017

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Vasodilator-stimulated phosphoprotein (VASP) is a processive actin polymerase with roles in the control of cell shape and cell migration. Through interaction with the cytoskeletal adaptor protein Zyxin, VASP can localize to damaged stress fibers where it serves to repair and reinforce these structures. VASP localization is mediated by its N-terminal Ena/VASP homology (EVH1) domain, which binds to the (W/F)PxφP motif (most commonly occurring as FPPPP) found in cytoskeletal proteins such as vinculin, lamellipodin, and Zyxin. Sequentially close clusters of four or five of these motifs frequently occur, as in the proline rich region of Zyxin with four such motifs. This suggests that tetrameric VASP might bind very tightly to Zyxin through avidity, with all four EVH1 domains binding to a single Zyxin molecule. Here, quantitative nuclear magnetic resonance titration analysis reveals a dominant bivalent 1:1 (Zyxin:EVH1) interaction between the Zyxin proline rich region and the VASP EVH1 domain that utilizes the EVH1 canonical binding site and a novel secondary binding site on the opposite face of the EVH1 domain. We further show that binding to the secondary binding site is specifically inhibited by mutation of VASP EVH1 domain residue Y39 to E, which mimics Abl-induced phosphorylation of Y39. On the basis of these findings, we propose a model in which phosphorylation of Y39 acts as a stoichiometry switch that governs binding partner selection by the constitutive VASP tetramer. These results have broader implications for other multivalent VASP EVH1 domain binding partners and for furthering our understanding of the role of Y39 phosphorylation in regulating VASP localization and cellular function.

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“…This region has previously been implicated in function, as mutation of the nearby Y39 altered the co-localization of and interaction between VASP and Zyxin. 23 …”

Section: Resultsmentioning

confidence: 99%

A Noncanonical Binding Site in the EVH1 Domain of Vasodilator-Stimulated Phosphoprotein Regulates Its Interactions with the Proline Rich Region of Zyxin

2017

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“…Abl interactor-1 (Abi-1) promotes the interaction between Abl and Ena/VASP proteins and mediates phosphorylation of VASP by Abl at Y39. 44,45 Abl also phosphorylates other members of this protein family, including Mena at Y296. 44 Another substrate of Abl is lamellipodin (Lpd) and its phosphorylation recruits Ena/VASP proteins (Mena, VASP, EVL) to the leading edge of cells.…”

Section: Phosphorylation At Y39 and Potential Function In Cell Migrationmentioning

confidence: 98%

Regulation of VASP by phosphorylation

Döppler

Störz

2013

Cell Adhesion & Migration

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Phosphorylations control all aspects of vasodilator-stimulated phospho-protein (VASP) function. Mapped phosphorylation sites include Y39, S157, S239, T278, and S322, and multiple kinases have been shown to mediate their phosphorylation. Recently, Protein Kinase D1 (PKD1) as a direct kinase for S157 and S322 joined this group. While S157 phosphorylation generally seems to serve as a signal for membrane localization, phosphorylations at S322 or at S239 and T278 have opposite effects on F-actin accumulation. In migrating cells, S322 phosphorylation increases filopodia numbers and length, while S239/T278 phosphorylations decrease these and also disrupt formation of focal adhesions. Therefore, the kinases mediating these phosphorylations can be seen as switches needed to facilitate cell motility.

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“…For example, GRB2 and SHP2 both interact with IRS1 Y895 (68) in vivo, and are predicted here to interact with the Y39 peptide RVQIYHNPTAN within vasodilator-stimulated phosphoprotein (VASP). ABL1 also binds with highaffinity to both peptides, and is known to phosphorylate VASP Y39 in vivo (69). Although IRS1 Y895 contains no hot-spot residues for NCK1, VASP Y39 contains a ϩ3P.…”

Section: Figmentioning

confidence: 99%

The Development and Application of a Quantitative Peptide Microarray Based Approach to Protein Interaction Domain Specificity Space

Engelmann

Kim

Wang

et al. 2014

Molecular & Cellular Proteomics

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Protein interaction domain (PID) linear peptide motif interactions direct diverse cellular processes in a specific and coordinated fashion. PID specificity, or the interaction selectivity derived from affinity preferences between possible PID-peptide pairs is the basis of this ability. Here, we develop an integrated experimental and computational cellulose peptide conjugate microarray (CPCMA) based approach for the high throughput analysis of PID specificity that provides unprecedented quantitative resolution and reproducibility. As a test system, we quantify the specificity preferences of four Src Homology 2 domains and 124 physiological phosphopeptides to produce a novel quantitative interactome. The quantitative data set covers a broad affinity range, is highly precise, and agrees well with orthogonal biophysical validation, in vivo interactions, and peptide library trained algorithm predictions. In contrast to preceding approaches, the CPCMAs proved capable of confidently assigning interactions into affinity categories, resolving the subtle affinity contributions of residue correlations, and yielded predictive peptide motif affinity matrices. Unique CPCMA enabled modes of systems level analysis reveal a physiological interactome with expected node degree value decreasing as a function of affinity, resulting in minimal high affinity binding overlap between domains; uncover that Src Homology 2 domains bind ligands with a similar average affinity yet strikingly different levels of promiscuity and binding dynamic range; and parse with unprecedented quantitative resolution contextual factors directing specificity. The CPCMA platform promises broad application within the fields of PID specificity, synthetic biology, specificity focused drug design, and network biology. Molecular & Cellular Proteomics 13: 10.1074/mcp.O114.038695, 3647-3662, 2014. Protein interaction domains (PIDs)1 often compete for the same linear motif binding sites across a range of affinities, resulting in many potential interactions that may enable the rapid assembly and disassembly of signaling proteins in response to external and internal cues (1, 2). PID-peptide interactions have small binding interfaces, resulting in moderate affinity interactions mediated primarily by a few amino acid "hot-spots" within motifs specific for a particular PID family (3-5). The power of individual residues to direct interactions, the absence of structural constraint for linear motifs, and the modularity of PIDs has enabled the rapid evolution of these networks resulting in many large multimember PID families in higher eukaryotes (6 -9). For these large families dedicated to the recognition of similar ligands, PID specificity-or the interaction selectivity derived from affinity preferences between possible PID-peptide pairs-underpins the effective conveyance of specific cell signals. High throughput interaction mapping efforts are used to decipher how this PID "specificity space" is populated, thereby providing insight into protein function and the principles ...

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Abi-1-bridged tyrosine phosphorylation of VASP by Abelson kinase impairs association of VASP to focal adhesions and regulates leukaemic cell adhesion

Cited by 37 publications

References 60 publications

A Noncanonical Binding Site in the EVH1 Domain of Vasodilator-Stimulated Phosphoprotein Regulates Its Interactions with the Proline Rich Region of Zyxin

A Noncanonical Binding Site in the EVH1 Domain of Vasodilator-Stimulated Phosphoprotein Regulates Its Interactions with the Proline Rich Region of Zyxin

Regulation of VASP by phosphorylation

The Development and Application of a Quantitative Peptide Microarray Based Approach to Protein Interaction Domain Specificity Space

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