The Focal Adhesion Targeting Domain of Focal Adhesion Kinase Contains a Hinge Region that Modulates Tyrosine 926 Phosphorylation

Prutzman, Kirk C.; Gao, Guo-Jian; King, Michelle L.; Iyer, Vidhya V.; Mueller, Geoffrey A.; Schaller, Michael D.; Campbell, Sharon L.

doi:10.1016/j.str.2004.02.028

Cited by 38 publications

(46 citation statements)

References 58 publications

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“…H1 opening has subsequently been observed in several studies (15,32,33). The conformational strain in this hinge region was experimentally apparent (34,35) and relieved in the open or H1-swapped dimeric conformation of Pro 944 -APP (27,35). The open state would allow Tyr 925 phosphorylation and subsequent binding to Grb2.…”

Section: Focal Adhesion Kinase (Fak)mentioning

confidence: 79%

Conformational Dynamics of the Focal Adhesion Targeting Domain Control Specific Functions of Focal Adhesion Kinase in Cells

Kadaré

Gervasi

Brami‐Cherrier

et al. 2015

Journal of Biological Chemistry

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Section: Focal Adhesion Kinase (Fak)mentioning

confidence: 79%

Conformational Dynamics of the Focal Adhesion Targeting Domain Control Specific Functions of Focal Adhesion Kinase in Cells

Kadaré

Gervasi

Brami‐Cherrier

et al. 2015

Journal of Biological Chemistry

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“…Of these two sites, Tyr-925 phosphorylation by Src has been implicated as an important event in adhesion-stimulated FAK signaling by promoting an interaction with the adaptor Grb2 [Schlaepfer et al, 1994;Schlaepfer and Hunter, 1996]. Structural studies showing that Tyr-925 occupies a position in the functional FAK FAT domain where it would be inaccessible indicate that phosphorylation of this site may be of very low stoichiometry in adhesions and occur only in the context of a transient open conformation [Arold et al, 2002;Prutzman et al, 2004]. The mechanism of adhesiondependent activation of FAK appears to involve the interaction(s) of the FERM domain with clustered integrins and/or integrin-associated proteins in nascent adhesion sites, thereby releasing an autoinhibitory interaction of the FERM domain with the FAK kinase domain [Cooper et al, 2003;Dunty et al, 2004;Cohen and Guan, 2005].…”

Section: Discussionmentioning

confidence: 99%

A FAK/Src chimera with gain‐of‐function properties promotes formation of large peripheral adhesions associated with dynamic actin assembly

Siesser

Meenderink

Ryzhova

et al. 2007

Cell Motil. Cytoskeleton

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Formation of a complex between the tyrosine kinases FAK and Src is a key integrin-mediated signaling event implicated in cell motility, survival, and proliferation. Past studies indicate that FAK functions in the complex primarily as a "scaffold," acting to recruit and activate Src within cell/matrix adhesions. To study the cellular impact of FAK-associated Src signaling we developed a novel gainof-function approach that involves expressing a chimeric protein with the FAK kinase domain replaced by the Src kinase domain. This FAK/Src chimera is subject to adhesion-dependent activation and promotes tyrosine phosphorylation of p130Cas and paxillin to higher steady-state levels than is achieved by wild-type FAK. When expressed in FAK -/-mouse embryo fibroblasts, the FAK/Src chimera resulted in a striking cellular phenotype characterized by unusual large peripheral adhesions, enhanced adhesive strength, and greatly reduced motility. Live cell imaging of the chimeraexpressing FAK -/-cells provided evidence that the large peripheral adhesions are associated with a dynamic actin assembly process that is sensitive to a Src-selective inhibitor. These findings suggest that FAK-associated Src kinase activity has the capacity to promote adhesion integrity and actin assembly.

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“…It has been demonstrated that the FAK FAT domain features helix H1 swapping dynamics and dimer formation (25,40), although the biological importance of such a dimer in the context of full-length FAK is not very clear. However, unlike the FAT domain, our NMR data clearly indicated that PBD existed as a monomer in solution.…”

Section: Solution Structure Of the Git1 Pbd Is A Four-helix Bundle-mentioning

confidence: 99%

GIT1 Paxillin-binding Domain Is a Four-helix Bundle, and It Binds to Both Paxillin LD2 and LD4 Motifs

Zhang

Simmerman

Guibao

et al. 2008

Journal of Biological Chemistry

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The G protein-coupled receptor kinase-interacting protein 1 (GIT1) is a multidomain protein that plays an important role in cell adhesion, motility, cytoskeletal remodeling, and membrane trafficking. GIT1 mediates the localization of the p21-activated kinase (PAK) and PAK-interactive exchange factor to focal adhesions, and its activation is regulated by the interaction between its C-terminal paxillin-binding domain (PBD) and the LD motifs of paxillin. In this study, we determined the solution structure of rat GIT1 PBD by NMR spectroscopy. The PBD folds into a four-helix bundle, which is structurally similar to the focal adhesion targeting and vinculin tail domains. Previous studies showed that GIT1 interacts with paxillin through the LD4 motif. Here, we demonstrated that in addition to the LD4 motif, the GIT1 PBD can also bind to the paxillin LD2 motif, and both LD2 and LD4 motifs competitively target the same site on the PBD surface. We also revealed that paxillin Ser 272 phosphorylation does not influence GIT1 PBD binding in vitro. These results are in agreement with the notion that phosphorylation of paxillin Ser 272 plays an essential role in regulating focal adhesion turnover.Cells attach and communicate with the extracellular matrix through membrane peripheral proteins that form focal adhesions (FAs) 3 (1, 2). Cell motility is regulated through the alternative assembly and disassembly of FAs and cytoskeletal proteins (3). The dynamics of FAs are controlled by the signaling of different adhesion molecules such as focal adhesion kinase (FAK), paxillin, the G protein-coupled kinase-interacting (GIT) protein, and p21-activated kinase (PAK) (4 -7), whereas cytoskeletal remodeling is regulated by small GTPases of the Ras and Rho family, such as Rac1, Cdc42, and RhoA (8 -10).GIT proteins play an important role in initiating the disassembly of FAs (11,12). Both members of the GIT protein family, GIT1 and GIT2/p95-PKL, have an N-terminal Arf GTPase-activating protein domain, a Spa2-homology domain, a coiled-coil domain, and a C-terminal paxillin-binding domain (PBD). Previous studies have shown that the Spa2 homology domain binds the PAK⅐PIX complex, and the PBD binds paxillin (11,(13)(14)(15). GITs, functioning as scaffold proteins, target the PAK complex into FAs by binding with paxillin via their PBDs (11,13,16). GIT PBDs span about 130 amino acids and are highly conserved among species (17). Recently, a low-resolution structural model for the GIT1 PBD was derived from small-angle x-ray scattering and homology modeling, based on the structure of the FAK focal adhesion targeting (FAT) domain, which is a four-helix bundle protein (15). Mutagenesis studies suggest that paxillin binds the GIT1 PBD through the putative helices H1 and H4 (15). However, a high-resolution structure of the GIT1 PBD is unavailable, and the mechanism of paxillin-GIT interaction remains unclear.Paxillin is one of the major binding partners of GIT proteins in FAs, functioning as an elongated adaptor protein that links actin filaments with ...

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The Focal Adhesion Targeting Domain of Focal Adhesion Kinase Contains a Hinge Region that Modulates Tyrosine 926 Phosphorylation

Cited by 38 publications

References 58 publications

Conformational Dynamics of the Focal Adhesion Targeting Domain Control Specific Functions of Focal Adhesion Kinase in Cells

Conformational Dynamics of the Focal Adhesion Targeting Domain Control Specific Functions of Focal Adhesion Kinase in Cells

A FAK/Src chimera with gain‐of‐function properties promotes formation of large peripheral adhesions associated with dynamic actin assembly

GIT1 Paxillin-binding Domain Is a Four-helix Bundle, and It Binds to Both Paxillin LD2 and LD4 Motifs

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