Multiple paxillin binding sites regulate FAK function

Scheswohl, Danielle M; Harrell, Jessica R.; Rajfur, Zenon; Gao, Guo-Jian; Campbell, Sharon L.; Schaller, Michael D.

doi:10.1186/1750-2187-3-1

Cited by 69 publications

(93 citation statements)

References 41 publications

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“…The paxillin LIM domain has also been shown to bind α, and the less abundant, γ-tubulin [51,107]. These interactions, combined with the ability of the LD domain to bind [51,107]. This apparent cooperation between the two structural domains of paxillin can also be seen in the localization and activation of the non-receptor tyrosine kinase, FAK.…”

Section: Paxillin Structure and Functionmentioning

confidence: 99%

“…However, the heterogeneity of the adhesion complex does not end with differential protein composition and localization. To a large degree, the signaling plasticity inherent to these structures can be seen as a bi-product of temporallyinduced phosphorylated isoforms, or phospho-isoforms, of focal adhesion proteins [51,52]. For example, FAK activation following integrin binding to the extracellular matrix, induces its autophosphorylation at Tyr(Y)397, creating Src-homology-2 (SH2) sites for binding partners Src, PI3K, Grb7 and phospholipase-Cγ [51].…”

Section: The Focal Adhesion As a Signaling Nexusmentioning

confidence: 99%

“…To a large degree, the signaling plasticity inherent to these structures can be seen as a bi-product of temporallyinduced phosphorylated isoforms, or phospho-isoforms, of focal adhesion proteins [51,52]. For example, FAK activation following integrin binding to the extracellular matrix, induces its autophosphorylation at Tyr(Y)397, creating Src-homology-2 (SH2) sites for binding partners Src, PI3K, Grb7 and phospholipase-Cγ [51]. Subsequent Src-mediated phosphorylation of FAK at Y576/Y577/Y861/Y925 further increases its catalytic activity, propagating downstream signaling cascades [51][52][53][54].…”

Section: The Focal Adhesion As a Signaling Nexusmentioning

confidence: 99%

“…Accordingly, several paxillin LIM-domain binding partners have been identified, such as the tyrosine phosphatase-PEST (PTP-PEST) and the non-receptor tyrosine kinase Csk (C-terminal Src kinase), both of which function to regulate paxillin subcellular targeting and consequently, focal adhesion architecture [66,85]. The paxillin LIM domain has also been shown to bind α, and the less abundant, γ-tubulin [51,107]. These interactions, combined with the ability of the LD domain to bind [51,107].…”

Section: Paxillin Structure and Functionmentioning

confidence: 99%

“…This apparent cooperation between the two structural domains of paxillin can also be seen in the localization and activation of the non-receptor tyrosine kinase, FAK. Failure of FAK to bind paxillin has been shown to result in decreased FAK focal adhesion localization and tyrosine phosphorylation [51,52,66,108]. Characterization of the paxillin-FAK interaction shows that it is the C-terminal focal adhesion targeting domain of FAK, specifically the paxillin binding sequences 1 and 2 (PBS 1 and 2) within this domain, that are capable of binding both the second and the fourth LD motifs of paxillin with equal affinity [51,108].…”

Section: Paxillin Structure and Functionmentioning

confidence: 99%

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SLK-mediated phosphorylation of paxillin is required for focal adhesion turnover and cell migration

Baron

et al. 2012

Oncogene

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Section: Paxillin Structure and Functionmentioning

confidence: 99%

Section: The Focal Adhesion As a Signaling Nexusmentioning

confidence: 99%

Section: The Focal Adhesion As a Signaling Nexusmentioning

confidence: 99%

Section: Paxillin Structure and Functionmentioning

confidence: 99%

Section: Paxillin Structure and Functionmentioning

confidence: 99%

See 3 more Smart Citations

SLK-mediated phosphorylation of paxillin is required for focal adhesion turnover and cell migration

Baron

et al. 2012

Oncogene

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Dynamics of focal adhesions and reorganization of F‐actin in VEGF‐stimulated NSCs under varying differentiation states

Lyu

et al. 2013

J of Cellular Biochemistry

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Precise migration of neural stem/progenitor cells (NSCs) is crucially important for neurogenesis and repair in the nervous system. However, the detailed mechanisms are not clear. Our previous results showed that NSCs in varying differentiation states possess different migratory ability to vascular endothelial growth factor (VEGF). In this study, we demonstrate the different dynamics of focal adhesions (FAs) and reorganization of F-actin in NSCs during spreading and migration stimulated by VEGF. We found that the migrating NSCs of 0.5 and 1 day differentiation possess more FAs at leading edge than cells of other states. Moreover, the phosphorylation of focal adhesion kinase (FAK) and paxillin in NSCs correlates closely with their differentiation states. VEGF promotes FA formation with broad lamellipodium generation at the leading edge in chemotaxing cells of 0, 0.5, and 1 day differentiation, but not in cells of 3 days differentiation. Furthermore, cells of 1 day differentiation show a maximal asymmetry of FAs between lamella and cell rear, orchestrating cell polarization and directional migration. Time-lapse video analysis shows that the disassembly of FAs and the cell tail detachment in NSCs of 1 day differentiation are more rapid, along with the concurrent enlarged size of FAs at the leading edge, leading to the most effective chemotactic response to VEGF. Collectively, these results indicate that the dynamics of FAs and reorganization of F-actin in NSCs that undergo directional migration correlate closely with their differentiation states, contributing to the different chemotactic responses of these cells to VEGF.

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Recognition of LD motifs by the focal adhesion targeting domains of focal adhesion kinase and proline‐rich tyrosine kinase 2‐beta: Insights from molecular dynamics simulations

et al. 2020

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The focal adhesion kinase (FAK) and the proline‐rich tyrosine kinase 2‐beta (PYK2) are implicated in cancer progression and metastasis and represent promising biomarkers and targets for cancer therapy. FAK and PYK2 are recruited to focal adhesions (FAs) via interactions between their FA targeting (FAT) domains and conserved segments (LD motifs) on the proteins Paxillin, Leupaxin, and Hic‐5. A promising new approach for the inhibition of FAK and PYK2 targets interactions of the FAK domains with proteins that promote localization at FAs. Advances toward this goal include the development of surface plasmon resonance, heteronuclear single quantum coherence nuclear magnetic resonance (HSQC‐NMR) and fluorescence polarization assays for the identification of fragments or compounds interfering with the FAK‐Paxillin interaction. We have recently validated this strategy, showing that Paxillin mimicking polypeptides with 2 to 3 LD motifs displace FAK from FAs and block kinase‐dependent and independent functions of FAK, including downstream integrin signaling and FA localization of the protein p130Cas. In the present work we study by all‐atom molecular dynamics simulations the recognition of peptides with the Paxillin and Leupaxin LD motifs by the FAK‐FAT and PYK2‐FAT domains. Our simulations and free‐energy analysis interpret experimental data on binding of Paxillin and Leupaxin LD motifs at FAK‐FAT and PYK2‐FAT binding sites, and assess the roles of consensus LD regions and flanking residues. Our results can assist in the design of effective inhibitory peptides of the FAK‐FAT: Paxillin and PYK2‐FAT:Leupaxin complexes and the construction of pharmacophore models for the discovery of potential small‐molecule inhibitors of the FAK‐FAT and PYK2‐FAT focal adhesion based functions.

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Multiple paxillin binding sites regulate FAK function

Cited by 69 publications

References 41 publications

SLK-mediated phosphorylation of paxillin is required for focal adhesion turnover and cell migration

SLK-mediated phosphorylation of paxillin is required for focal adhesion turnover and cell migration

Dynamics of focal adhesions and reorganization of F‐actin in VEGF‐stimulated NSCs under varying differentiation states

Recognition of LD motifs by the focal adhesion targeting domains of focal adhesion kinase and proline‐rich tyrosine kinase 2‐beta: Insights from molecular dynamics simulations

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