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Definition of a consensus integrin adhesome and its dynamics during adhesion complex assembly and disassembly.

Horton ER, Byron A, Askari JA, Ng DH, Millon-Frémillon A, Robertson J, Koper EJ, Paul NR, Warwood S, Knight D, Humphries JD, Humphries MJ - Nat. Cell Biol. (2015)

Bottom Line: Here, we have integrated several IAC proteomes and generated a 2,412-protein integrin adhesome.Analysis of this data set reveals the functional diversity of proteins in IACs and establishes a consensus adhesome of 60 proteins.The definition of this consensus view of integrin adhesome components provides a resource for the research community.

View Article: PubMed Central - PubMed

Affiliation: Wellcome Trust Centre for Cell-Matrix Research, Faculty of Life Sciences, University of Manchester, Manchester M13 9PT, UK.

ABSTRACT
Integrin receptor activation initiates the formation of integrin adhesion complexes (IACs) at the cell membrane that transduce adhesion-dependent signals to control a multitude of cellular functions. Proteomic analyses of isolated IACs have revealed an unanticipated molecular complexity; however, a global view of the consensus composition and dynamics of IACs is lacking. Here, we have integrated several IAC proteomes and generated a 2,412-protein integrin adhesome. Analysis of this data set reveals the functional diversity of proteins in IACs and establishes a consensus adhesome of 60 proteins. The consensus adhesome is likely to represent a core cell adhesion machinery, centred around four axes comprising ILK-PINCH-kindlin, FAK-paxillin, talin-vinculin and α-actinin-zyxin-VASP, and includes underappreciated IAC components such as Rsu-1 and caldesmon. Proteomic quantification of IAC assembly and disassembly detailed the compositional dynamics of the core cell adhesion machinery. The definition of this consensus view of integrin adhesome components provides a resource for the research community.

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Functional enrichment map of the consensus integrin adhesome. (a,b) Overrepresented biological process (a) and cellular component (b) terms from proteins identified in the consensus adhesome were hierarchically clustered according to proteomic dataset occurrence. This identified clusters of similarly detected proteins associated with a similar set of functional terms. Related terms are summarised (black bars). Proteins are labelled with gene names for clarity (see Supplementary Table 4 for details).
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Figure 3: Functional enrichment map of the consensus integrin adhesome. (a,b) Overrepresented biological process (a) and cellular component (b) terms from proteins identified in the consensus adhesome were hierarchically clustered according to proteomic dataset occurrence. This identified clusters of similarly detected proteins associated with a similar set of functional terms. Related terms are summarised (black bars). Proteins are labelled with gene names for clarity (see Supplementary Table 4 for details).

Mentions: The meta-adhesome provides a resource detailing global IAC composition from multiple cell types and experimental designs. Proteins with diverse cellular functions were detected in the meta-adhesome, but the most robustly detected proteins were overrepresented for numerous adhesion-related functions (Supplementary Fig. 3). To identify the core set of IAC components, and thereby aid the identification of key nodes controlling adhesive functions20, we examined proteins identified in at least five datasets (excluding ECM components), which resulted in a consensus integrin adhesome comprising 60 proteins (Supplementary Table 4). Pathways regulating adhesion-related functions were the most significantly enriched in the consensus adhesome (Fig. 3, Supplementary Table 5), and there was overrepresentation of actin-binding domains and, most significantly, LIM domains, which have been shown previously to be involved in force recognition at adhesion sites12,15,21-24 (Supplementary Tables 4, 5). Nine consensus adhesome genes (15%) had links to inherited diseases (Supplementary Table 4), including seven also identified in a recent report4 and two others (α-actinin-4 and cyclophilin B) associated with glomerular disease and bone disorders, which have previously been linked to adhesome genes4.


Definition of a consensus integrin adhesome and its dynamics during adhesion complex assembly and disassembly.

Horton ER, Byron A, Askari JA, Ng DH, Millon-Frémillon A, Robertson J, Koper EJ, Paul NR, Warwood S, Knight D, Humphries JD, Humphries MJ - Nat. Cell Biol. (2015)

Functional enrichment map of the consensus integrin adhesome. (a,b) Overrepresented biological process (a) and cellular component (b) terms from proteins identified in the consensus adhesome were hierarchically clustered according to proteomic dataset occurrence. This identified clusters of similarly detected proteins associated with a similar set of functional terms. Related terms are summarised (black bars). Proteins are labelled with gene names for clarity (see Supplementary Table 4 for details).
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Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4663675&req=5

Figure 3: Functional enrichment map of the consensus integrin adhesome. (a,b) Overrepresented biological process (a) and cellular component (b) terms from proteins identified in the consensus adhesome were hierarchically clustered according to proteomic dataset occurrence. This identified clusters of similarly detected proteins associated with a similar set of functional terms. Related terms are summarised (black bars). Proteins are labelled with gene names for clarity (see Supplementary Table 4 for details).
Mentions: The meta-adhesome provides a resource detailing global IAC composition from multiple cell types and experimental designs. Proteins with diverse cellular functions were detected in the meta-adhesome, but the most robustly detected proteins were overrepresented for numerous adhesion-related functions (Supplementary Fig. 3). To identify the core set of IAC components, and thereby aid the identification of key nodes controlling adhesive functions20, we examined proteins identified in at least five datasets (excluding ECM components), which resulted in a consensus integrin adhesome comprising 60 proteins (Supplementary Table 4). Pathways regulating adhesion-related functions were the most significantly enriched in the consensus adhesome (Fig. 3, Supplementary Table 5), and there was overrepresentation of actin-binding domains and, most significantly, LIM domains, which have been shown previously to be involved in force recognition at adhesion sites12,15,21-24 (Supplementary Tables 4, 5). Nine consensus adhesome genes (15%) had links to inherited diseases (Supplementary Table 4), including seven also identified in a recent report4 and two others (α-actinin-4 and cyclophilin B) associated with glomerular disease and bone disorders, which have previously been linked to adhesome genes4.

Bottom Line: Here, we have integrated several IAC proteomes and generated a 2,412-protein integrin adhesome.Analysis of this data set reveals the functional diversity of proteins in IACs and establishes a consensus adhesome of 60 proteins.The definition of this consensus view of integrin adhesome components provides a resource for the research community.

View Article: PubMed Central - PubMed

Affiliation: Wellcome Trust Centre for Cell-Matrix Research, Faculty of Life Sciences, University of Manchester, Manchester M13 9PT, UK.

ABSTRACT
Integrin receptor activation initiates the formation of integrin adhesion complexes (IACs) at the cell membrane that transduce adhesion-dependent signals to control a multitude of cellular functions. Proteomic analyses of isolated IACs have revealed an unanticipated molecular complexity; however, a global view of the consensus composition and dynamics of IACs is lacking. Here, we have integrated several IAC proteomes and generated a 2,412-protein integrin adhesome. Analysis of this data set reveals the functional diversity of proteins in IACs and establishes a consensus adhesome of 60 proteins. The consensus adhesome is likely to represent a core cell adhesion machinery, centred around four axes comprising ILK-PINCH-kindlin, FAK-paxillin, talin-vinculin and α-actinin-zyxin-VASP, and includes underappreciated IAC components such as Rsu-1 and caldesmon. Proteomic quantification of IAC assembly and disassembly detailed the compositional dynamics of the core cell adhesion machinery. The definition of this consensus view of integrin adhesome components provides a resource for the research community.

Show MeSH
Related in: MedlinePlus