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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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Curated network model of the consensus integrin adhesome. Protein-protein interaction network of the consensus adhesome. Interactions were manually validated and scored (high, medium, low) according to the level of experimental evidence for that interaction, shown by the thickness and saturation of the grey edges (see Supplementary Table 6). Thick black node border indicates literature-curated adhesome4 protein. Yellow node indicates actin-binding protein. The specific isoforms and subunits of proteins identified are detailed in Supplementary Table 4 by gene name. For clarity, α-actinin is depicted as one node, even though two α-actinin isoforms (α-actinin-1 and -4) were identified. Actin is depicted for illustrative purposes but was not present in the consensus adhesome. The network comprised 41 proteins with 92 interactions, excluding actin binding. Unconnected components or components with only one low-evidence interaction are not shown in the network; proteins unconnected to the main network were ALYREF, BRIX1, DDX18, DDX27, DIMT1, DNAJB1, FAU, FEN1, H1FX, HP1BP3, LIMD1, MRTO4, POLDIP3, RPL23A, SIPA1 and SYNCRIP; proteins connected to the network with a single low-evidence interaction were P4HB and PPIB.
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Figure 4: Curated network model of the consensus integrin adhesome. Protein-protein interaction network of the consensus adhesome. Interactions were manually validated and scored (high, medium, low) according to the level of experimental evidence for that interaction, shown by the thickness and saturation of the grey edges (see Supplementary Table 6). Thick black node border indicates literature-curated adhesome4 protein. Yellow node indicates actin-binding protein. The specific isoforms and subunits of proteins identified are detailed in Supplementary Table 4 by gene name. For clarity, α-actinin is depicted as one node, even though two α-actinin isoforms (α-actinin-1 and -4) were identified. Actin is depicted for illustrative purposes but was not present in the consensus adhesome. The network comprised 41 proteins with 92 interactions, excluding actin binding. Unconnected components or components with only one low-evidence interaction are not shown in the network; proteins unconnected to the main network were ALYREF, BRIX1, DDX18, DDX27, DIMT1, DNAJB1, FAU, FEN1, H1FX, HP1BP3, LIMD1, MRTO4, POLDIP3, RPL23A, SIPA1 and SYNCRIP; proteins connected to the network with a single low-evidence interaction were P4HB and PPIB.

Mentions: To validate further the consensus integrin adhesome network, interactions between proteins were scored according to the level of supporting experimental evidence (Supplementary Table 6). The resulting interaction network contained many known IAC components, including 31 literature-curated adhesome members4 (black borders, Fig. 4; Supplementary Table 4). The most connected proteins were literature-curated adhesome4 components (proposed interactions; FAK, 15; β1 integrin, 13; paxillin, 12), which may be because these proteins have been studied more extensively than others25. An emergent property of the consensus adhesome network was that it broadly clustered into four theoretical modules based on currently known signalling axes and links from integrins to actin reported in the literature (Fig. 4). The first module contained α-actinin and zyxin family members. The second module contained vinculin, talin and the vinculin-binding proteins vinexin and ponsin. Vinculin contained the highest number of high-evidence interactions (seven) and associated with many proteins in the third module containing FAK and paxillin. The final module consisted of two submodules connected via a kindlin-ILK interaction. In addition, non-consensus meta-adhesome proteins are known to interact with consensus components (Supplementary Table 7) and are therefore also likely to be involved in regulating the integrin-actin connection.


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)

Curated network model of the consensus integrin adhesome. Protein-protein interaction network of the consensus adhesome. Interactions were manually validated and scored (high, medium, low) according to the level of experimental evidence for that interaction, shown by the thickness and saturation of the grey edges (see Supplementary Table 6). Thick black node border indicates literature-curated adhesome4 protein. Yellow node indicates actin-binding protein. The specific isoforms and subunits of proteins identified are detailed in Supplementary Table 4 by gene name. For clarity, α-actinin is depicted as one node, even though two α-actinin isoforms (α-actinin-1 and -4) were identified. Actin is depicted for illustrative purposes but was not present in the consensus adhesome. The network comprised 41 proteins with 92 interactions, excluding actin binding. Unconnected components or components with only one low-evidence interaction are not shown in the network; proteins unconnected to the main network were ALYREF, BRIX1, DDX18, DDX27, DIMT1, DNAJB1, FAU, FEN1, H1FX, HP1BP3, LIMD1, MRTO4, POLDIP3, RPL23A, SIPA1 and SYNCRIP; proteins connected to the network with a single low-evidence interaction were P4HB and PPIB.
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Related In: Results  -  Collection

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Figure 4: Curated network model of the consensus integrin adhesome. Protein-protein interaction network of the consensus adhesome. Interactions were manually validated and scored (high, medium, low) according to the level of experimental evidence for that interaction, shown by the thickness and saturation of the grey edges (see Supplementary Table 6). Thick black node border indicates literature-curated adhesome4 protein. Yellow node indicates actin-binding protein. The specific isoforms and subunits of proteins identified are detailed in Supplementary Table 4 by gene name. For clarity, α-actinin is depicted as one node, even though two α-actinin isoforms (α-actinin-1 and -4) were identified. Actin is depicted for illustrative purposes but was not present in the consensus adhesome. The network comprised 41 proteins with 92 interactions, excluding actin binding. Unconnected components or components with only one low-evidence interaction are not shown in the network; proteins unconnected to the main network were ALYREF, BRIX1, DDX18, DDX27, DIMT1, DNAJB1, FAU, FEN1, H1FX, HP1BP3, LIMD1, MRTO4, POLDIP3, RPL23A, SIPA1 and SYNCRIP; proteins connected to the network with a single low-evidence interaction were P4HB and PPIB.
Mentions: To validate further the consensus integrin adhesome network, interactions between proteins were scored according to the level of supporting experimental evidence (Supplementary Table 6). The resulting interaction network contained many known IAC components, including 31 literature-curated adhesome members4 (black borders, Fig. 4; Supplementary Table 4). The most connected proteins were literature-curated adhesome4 components (proposed interactions; FAK, 15; β1 integrin, 13; paxillin, 12), which may be because these proteins have been studied more extensively than others25. An emergent property of the consensus adhesome network was that it broadly clustered into four theoretical modules based on currently known signalling axes and links from integrins to actin reported in the literature (Fig. 4). The first module contained α-actinin and zyxin family members. The second module contained vinculin, talin and the vinculin-binding proteins vinexin and ponsin. Vinculin contained the highest number of high-evidence interactions (seven) and associated with many proteins in the third module containing FAK and paxillin. The final module consisted of two submodules connected via a kindlin-ILK interaction. In addition, non-consensus meta-adhesome proteins are known to interact with consensus components (Supplementary Table 7) and are therefore also likely to be involved in regulating the integrin-actin connection.

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