Doing (F/L)pppps: EVH1 domains and their proline-rich partners in cell polarity and migration

Renfranz, Patricia J.; Beckerle, Mary C.

doi:10.1016/s0955-0674(01)00299-x

Cited by 95 publications

(90 citation statements)

References 110 publications

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“…This is in agreement with our observation that stress fibers and cell adhesion are markedly increased in VASP(Ϫ/Ϫ) cardiac fibroblasts 2 and may contribute to the overall decrease in cell motility, like in the scratch assay. Interestingly, Kiosses and colleagues (40) suggested a model according to which regulated PAK activity is required for induction of tail retraction, which would be in line with the dysregulation of PAK activity and the motility phenotype of VASP(Ϫ/Ϫ) cells.…”

Section: Vasp-dependent Inhibition Of the Rac/pak Pathway-thesupporting

confidence: 93%

“…Together these data suggest a possible mode of VASP-dependent inhibition of Rac/PAK signaling through modulation of Trio-mediated guanine nucleotide exchange of Rac and/or Cdc42. Moreover, knock-out of the gene encoding the Trio interacting protein Tara causes cell spreading and stress fiber thickening (56), similar to VASP(Ϫ/Ϫ) cells, 2 and therefore puts additional emphasis on Trio as a putative player in the regulation of this phenotype.…”

Section: Vasp-dependent Inhibition Of the Rac/pak Pathway-thementioning

confidence: 99%

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Increased Spreading, Rac/p21-activated Kinase (PAK) Activity, and Compromised Cell Motility in Cells Deficient in Vasodilator-stimulated Phosphoprotein (VASP)

Arguinzonis¹,

Galler²,

Walter³

et al. 2002

Journal of Biological Chemistry

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Section: Vasp-dependent Inhibition Of the Rac/pak Pathway-thesupporting

confidence: 93%

Section: Vasp-dependent Inhibition Of the Rac/pak Pathway-thementioning

confidence: 99%

Increased Spreading, Rac/p21-activated Kinase (PAK) Activity, and Compromised Cell Motility in Cells Deficient in Vasodilator-stimulated Phosphoprotein (VASP)

Arguinzonis¹,

Galler²,

Walter³

et al. 2002

Journal of Biological Chemistry

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“…45,46 The Ena/VASP proteins are thought to play redundant roles in regulating actin cytoskeletal dynamics (reviewed by Renfranz and Beckerle 47 ). Interaction between FAT and Ena/VASP proteins is mediated via an EVH1 domain.…”

Section: Resultsmentioning

confidence: 99%

Positional cloning, association analysis and expression studies provide convergent evidence that the cadherin gene FAT contains a bipolar disorder susceptibility allele

et al. 2006

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A susceptibility locus for bipolar disorder was previously localized to chromosome 4q35 by genetic linkage analysis. We have applied a positional cloning strategy, combined with association analysis and provide evidence that a cadherin gene, FAT, confers susceptibility to bipolar disorder in four independent cohorts (allelic P-values range from 0.003 to 0.024). In two case-control cohorts, association was identified among bipolar cases with a family history of psychiatric illness, whereas in two cohorts of parent-proband trios, association was identified among bipolar cases who had exhibited psychosis. Pooled analysis of the case-control cohort data further supported association (P = 0.0002, summary odds ratio = 2.31, 95% CI: 1.49-3.59). We localized the bipolar-associated region of the FAT gene to an interval that encodes an intracellular EVH1 domain, a domain that interacts with Ena/VASP proteins, as well as putative b-catenin binding sites. Expression of Fat, Catnb (b-catenin), and the three genes (Enah, Evl and Vasp) encoding the Ena/VASP proteins, were investigated in mice following administration of the mood-stabilizing drugs, lithium and valproate. Fat was shown to be significantly downregulated (P = 0.027), and Catnb and Enah were significantly upregulated (P = 0.0003 and 0.005, respectively), in response to therapeutic doses of lithium. Using a protein interaction map, the expression of genes encoding murine homologs of the FAT (ft)-interacting proteins was investigated. Of 14 interacting molecules that showed expression following microarray analysis (including several members of the Wnt signaling pathway), eight showed significantly altered expression in response to therapeutic doses of lithium (binomial P = 0.004). Together, these data provide convergent evidence that FAT and its protein partners may be components of a molecular pathway involved in susceptibility to bipolar disorder.

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“…One is a structure-based "candidate" approach. VASP was a strong candidate because of the presence of multiple LPPPP motifs, potential docking sites for VASP (9,10), in migfilin proline-rich domain. To test whether VASP interacts with migfilin, we transfected HeLa cells with a vector encoding FLAG-migfilin and a vector lacking migfilin sequence as a control, respectively.…”

Section: Identification Of Vasp As a Binding Protein Of Migfilin-mentioning

confidence: 99%

Migfilin Interacts with Vasodilator-stimulated Phosphoprotein (VASP) and Regulates VASP Localization to Cell-Matrix Adhesions and Migration

Zhang

Gkretsi

et al. 2006

Journal of Biological Chemistry

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Cell migration is a complex process that is coordinately regulated by cell-matrix adhesion and actin cytoskeleton. We report here that migfilin, a recently identified component of cell-matrix adhesions, is a biphasic regulator of cell migration. Loss of migfilin impairs cell migration. Surprisingly, overexpression of migfilin also reduces cell migration. Molecularly, we have identified vasodilator-stimulated phosphoprotein (VASP) as a new migfilin-binding protein. The interaction is mediated by the VASP EVH1 domain and a single L 104 PPPPP site located within the migfilin proline-rich domain. Migfilin and VASP form a complex in both suspended and adhered cells, and in the latter, they co-localize in cell-matrix adhesions. Functionally, migfilin facilitates VASP localization to cell-matrix adhesions. Using two different approaches (VASP-binding defective migfilin mutants and small interfering RNA-mediated VASP knockdown), we show that the interaction with VASP is crucially involved in migfilin-mediated regulation of cell migration. Our results identify migfilin as an important regulator of cell migration and provide new information on the mechanism by which migfilin regulates this process.Cell migration is a tightly controlled process that is crucially involved in embryonic development, wound repair, and other physiological processes (1-4). Abnormal cell migration is an important causal factor for the pathogenesis and/or progression of a wide variety of diseases. Understanding how cells control their motility therefore is an important topic in molecular biology.Migfilin is a recently identified widely expressed focal adhesion protein that provides a link between cell-matrix adhesions and the actin cytoskeleton (5). Migfilin consists of three structurally distinct regions. The C-terminal region of migfilin is composed of three LIM domains, which mediates the interaction with Mig-2, a focal adhesion protein that is critically involved in cell-matrix adhesion and shape modulation (5, 6). The N-terminal region of migfilin interacts with filamin (5), an actin-binding protein whose deficiency or mutations cause defects in cell migration (7,8). Between the N-terminal and the C-terminal regions lies a proline-rich domain. Unlike the N-and C-terminal domains, however, neither the binding partners nor the functions of the migfilin proline-rich domain were known. Interestingly, some human cells express not only migfilin but also a splicing variant (termed as migfilin(s)) lacking the prolinerich domain (5).In this study, we have sought to identify proteins that interact with the proline-rich domain of migfilin and investigated the roles of migfilin in regulation of cell migration. Our results show that vasodilator-stimulated phosphoprotein (VASP), 2 an actin cytoskeletal regulatory protein (reviewed in Refs. 9 -11), interacts with the proline-rich domain of migfilin. Depletion of migfilin diminished VASP localization to cell-matrix adhesions and impairs cell migration. Surprisingly, overexpression of migfilin also reduces ce...

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Doing (F/L)pppps: EVH1 domains and their proline-rich partners in cell polarity and migration

Cited by 95 publications

References 110 publications

Increased Spreading, Rac/p21-activated Kinase (PAK) Activity, and Compromised Cell Motility in Cells Deficient in Vasodilator-stimulated Phosphoprotein (VASP)

Increased Spreading, Rac/p21-activated Kinase (PAK) Activity, and Compromised Cell Motility in Cells Deficient in Vasodilator-stimulated Phosphoprotein (VASP)

Positional cloning, association analysis and expression studies provide convergent evidence that the cadherin gene FAT contains a bipolar disorder susceptibility allele

Migfilin Interacts with Vasodilator-stimulated Phosphoprotein (VASP) and Regulates VASP Localization to Cell-Matrix Adhesions and Migration

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