Research highlights

Networks: The complexity of adhesion

Nature Reviews Molecular Cell Biology 8, 9 (01 September 2007) | doi:10.1038/nrm2237

The integrin adhesome interaction map. Reproduced with permission © (2007) Macmillan Publishers Ltd.

Cells sense multiple environmental signals through their matrix adhesion complexes, mediated via integrin receptors. These adhesions enable cells to behave differently on 2- and 3-dimensional matrices, distinguish between different extracellular matrix (ECM) components, detect differences in adhesive ligand density and respond to mechanical perturbation and surface rigidity. To understand the mechanisms that underlie these diverse responses, Zaidel-Bar and colleagues now provide a detailed description of the in silico integrin adhesome interaction map.

The authors used data derived from published experimental studies to outline the molecular basis of integrin-mediated adhesion and signalling by assembling a list of 156 components — 90 of which physically reside within adhesion sites and 66 'peripheral' components that interact with the intrinsic molecules and affect their activity and fate.

...provide a detailed description of the in silico integrin adhesome interaction map.

The adhesome network contains several functional groups, such as adaptor proteins, cytoskeletal proteins, actin-binding proteins, Ser/Thr kinases, Ser/Thr protein phosphatases, Tyr kinases, Tyr phosphatases, GTPases, GTPase-activating proteins and guanine-nucleotide exchange factors, transmembrane receptors and adhesion proteins. Information from literature searches and large protein–protein interaction databases, such as BIND and HPRD, was used to map most of the known interactions between these components. The network contains 690 links — 379 binding interactions (which are non-directional) and 311 signalling interactions, 213 of which are defined as activation interactions and 98 interactions that are defined as inhibitory.

Compared with other in silico mammalian intercellular networks, the adhesome network has a high links-per-node ratio and is characterized by dense connectivity within the network. These properties keep the network intact even after the removal of many nodes. Indeed, proteins with more than 20 interactions form more prominent hubs and are more essential for the function of the network than proteins with fewer interactions. For example, the loss of proteins with 30 or more potential interactions (such as integrin receptors) results in embryonic lethality in mice, whereas the loss of proteins with fewer than seven interactions does not have a devastating consequence.

Breaking the network into functional modules (subnets) — one structural and five regulatory subnets: Ser/Thr phosphorylation, Tyr phosphorylation, Rho GTPases, lipids and proteolytic activity — provided important insights into the fundamental design principles of the network. The authors estimate that more than half of the links that connect different adhesome components can be switched on and off by signalling elements; these include conformational, GTPase, phosphorylation and other types of switches.

Finally, the authors searched for unique 'design principles' that are significantly enriched in the adhesome network, and identified specific 'network motifs', which, via a 'scaffolding protein', link together proteins that can modify each other. Adhesome network motifs were found to be dynamic and to consist of binding interactions that can be regulated by on/off switches.

As the authors point out "...these findings can stimulate modelling and simulations that will further our understanding of how adhesion sites are formed and regulated, and how these molecular machines are capable of sensing the chemical and physical properties of their environment."

Author: Ekat Kritikou