Functional atlas of the integrin adhesome

Abstract

A detailed depiction of the 'integrin adhesome', consisting of a complex network of 156 components linked together and modified by 690 interactions is presented. Different views of the network reveal several functional 'subnets' that are involved in switching on or off many of the molecular interactions within the network, consequently affecting cell adhesion, migration and cytoskeletal organization. Examination of the adhesome network motifs reveals a relatively small number of key motifs, dominated by three-component complexes in which a scaffolding molecule recruits both a signalling molecule and its downstream target. We discuss the role of the different network modules in regulating the structural and signalling functions of cell-matrix adhesions. Top-down and bottom-up approaches for studying the integrin adhesomeCell-extracellular matrix (ECM) interactions are mediated through specialized subcellular sites that contain specific adhesion receptors, cytoskeletal elements and a wide variety of interconnecting adaptor proteins [1][2][3] . These adhesion complexes permit cells to sense multiple extracellular signals that specify the chemical identity, geometry and physical properties of the ECM 4,5 . Thus, cells behave differently on two-and three-dimensional matrices 6 , distinguish between different ECM components 7 , can detect differences in adhesive ligand density 8 , and respond to mechanical perturbation and surface rigidity 9,10 . Competing Financial Interests:The authors declare no competing financial interests.Website -www.adhesome.org contains the adhesome database of components and interactions with an interface that allows dynamical navigation between hyperlinked subnets created for each component and for many network motifs within the adhesome network.Publisher's Disclaimer: Disclaimer: Nature Publishing Group has a collaboration with the Cell Migration Consortium for the creation and maintenance of the Cell Migration gateway (http://www.cellmigration.org/), but has no role in generating or curating the Cell Migration Consortium database content. As always, Nature Cell Biology Editors have been fully independent and solely responsible for the editorial content and peer review of this Analysis article. NIH Public Access Author ManuscriptNat Cell Biol. Author manuscript; available in PMC 2009 August 31. Published in final edited form as:Nat Cell Biol. 2007 August ; 9(8): 858-867. doi:10.1038/ncb0807-858. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptTo understand the mechanisms underlying these diverse responses, in-depth characterization of individual proteins or pathways 11,12 , and collection of information about multiple components that concertedly form the presumed adhesome 13,14 , have been undertaken. Each of these approaches has limitations, and individually is unlikely to explain how the adhesion machinery senses environmental cues and responds to them. However, combining data from the two approaches could produce new mechanistic insights into the structu...

The tale of two talins – two isoforms to fine‐tune integrin signalling

“…This identified a network of > 240 proteins 1, 2, and additional adhesome proteins are constantly being discovered, many of which are cytoplasmic components that couple adhesions to numerous signalling cascades. These enable diverse intracellular responses, a process often referred to as ‘outside‐in’ signalling.…”

Conventional myosins – unconventional functions

“…5). However, despite the plethora of proteins defining the "integrin adhesome" (Zaidel-Bar et al 2007), myosins were not identified as intrinsic components. This implies that conventional myosins "act at a distance", a conclusion also reached by others (Vincente-Manzaneres et al 2007) who have used isoform-specific knockdown to examine the roles of M2A and M2B in migrating CHO.K1 cells.…”

“…Adhesion foci, comprising well over 100 different proteins (Zaidel-Bar et al 2007), act as physical contact points and signalling conduits between a cell and its surroundings. Key to adhesion are proteins such as integrin, vinculin or paxillin, which are found in adherent cells (Zamir and Geiger 2001) including those of neuronal origin, where they mediate adhesive interactions of the growth cone (Gomez et al 1996;de Curtis and Malanchini 1997;Renaudin et al 1999).…”

“…These adhesive foci are also sites for signal transmission between the extracellular matrix and the cell interior, using mechanisms that require myosin 2-generated contractility (Burridge and ChrzanowskaWodnicka 1996). At these sites, the universal myosin partner, actin, is usually present in the form of complex bundles, known as stress fibres; each stress fibre terminates at an adhesion focus and interacts with a plethora of associated proteins including adaptors, regulators and kinases amongst others, collectively known as the "integrin adhesome" (Zaidel-Bar et al 2007). Each adhesion focus acts as a mechanosensor, its size increasing in direct proportion to the forces sensed (Bershadsky et al 2003); typically, mammalian cells exert stress forces of the order 2-10 nN/μm 2 at these sites (Bershadsky et al 2003).…”

Structural and mechanical functions of integrins

“…For a detailed review of adaptor proteins that bind β-integrin cytoplasmic tails, the reader is referred to Legate and Fässler (2009). Collectively the composite of all the proteins, such as kinases, phosphatases and proteases, known to interact with integrins to assemble into FAs are loosely termed the integrin 'adhesome' (Zaidel-Bar et al 2007).…”