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The FERM domain: organizing the structure and function of FAK

Nature Reviews Molecular Cell Biology volume 11, pages 802–814 (2010)Cite this article

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Key Points

  • Focal adhesion kinase (FAK) is a scaffold and kinase protein that binds to itself and cellular partners through its four-point-one, ezrin, radixin, moesin (FERM) domain. Recent data on FAK structure and the sequence of activation have been deduced, largely from crystallographic and biosensor studies. These data have revealed that the activation sequence involves the release of FERM–kinase interactions, subsequent conformational changes, protein binding and key phosphorylation events at specific subcellular locations.

  • The FERM domain of FAK binds to cellular protein and lipid partners, and these are variously involved in catalytic activation and/or recruitment of FAK into macromolecular complexes in cells — predominantly at cortical adhesion structures, but also in the nucleus.

  • Among cytoplasmic FAK FERM domain binding partners recognized thus far are: phosphatidylinositol-4,5-bisphosphate (PtdIns(4,5)P2; generated by the action of phosphatidylinositol-4-phosphate 5-kinase type-1γ (PtdIns(4)P5KIγ)), which binds to the FERM domain and may trigger the activation cascade, perhaps along with molecular clustering, actin-related protein 3 (ARP3), receptor for activated kinase C 1 (RACK1), epidermal growth factor receptor (EGFR), c-Met, ezrin, epithelial and endothelial tyrosine kinase (ETK; also known as BMX), possibly insulin receptor substrate 1 (IRS1), JNK/SAPK-associated protein 1 (JSAP1; also known as JIP3) , and the β subunits of integrin cell–extracellular matrix receptors.

  • FAK is required for optimal signalling from the tyrosine kinase receptors EGFR and c-Met, and modulates cortical actin and nascent adhesions by binding to the ARP2/3 complex and the molecular scaffold RACK1. The FERM domain is implicated in these important FAK functions.

  • The FERM domains of FAK and PYK2 also bind to the tumour suppressor protein p53 and its regulator MDM2 in the nucleus on receipt of stress signals such as cell detachment. p53 degradation and survival can be promoted through these FERM-mediated interactions.

  • The findings above imply that the FAK FERM domain may control and coordinate cellular responses at the cell cortex and in the nucleus, potentially linking regulation of cell migration with the life and death choices that cells have to make. We speculate that the FERM domain may act as a 'sensor' and 'shuttle' of information and events occurring in and between distinct subcellular locations. From data in the literature on other FERM domain-containing proteins (FDCPs) and from sequence gazing, we speculate that a 'cortex to nuclear' information shuttle may be a more general function of FERM domains in biology, which could be exploited for therapy.

Abstract

Focal adhesion kinase (FAK) is a scaffold and tyrosine kinase protein that binds to itself and cellular partners through its four-point-one, ezrin, radixin, moesin (FERM) domain. Recent structural work reveals that regulatory protein partners convert auto-inhibited FAK into its active state by binding to its FERM domain. Further, the identity of FAK FERM domain-interacting proteins yields clues as to how FAK coordinates diverse cellular responses, including cell adhesion, polarization, migration, survival and death, and suggests that FERM domains might mediate information transfer between the cell cortex and nucleus. Importantly, the FAK FERM domain might act as a paradigm for the actions of other FERM domain-containing proteins.

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Figure 1: Phenogram of FERM domains.
Figure 2: Model of FAK activation.
Figure 3: Working models for integrin mediated FAK activation.
Figure 4: FAK signalling in subcellular space.

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Acknowledgements

The authors thank A. Welman for unpublished images. Work in the M.C.F. laboratory is funded by Cancer Research UK and Association for International Cancer Research, and in the M.J.E. laboratory by the US National Institutes of Health.

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Authors and Affiliations

  1. Edinburgh Cancer Research UK Centre, Institute of Genetics and Molecular Medicine, Western General Hospital, Crewe Road South, Edinburgh, EH4 2XR, UK

    Margaret C. Frame, Hitesh Patel & Bryan Serrels

  2. Cell Signalling and Adhesion Group, Structural Biology and Biocomputing Programme, Spanish National Cancer Research Centre (CNIO), C/ Melchor Fernández, lmagro, 3, Madrid, E-28029, Spain

    Daniel Lietha

  3. Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, 02115, Massachusetts, USA

    Michael J. Eck

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  1. Margaret C. Frame
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Glossary

Guanine nucleotide exchange factor

A protein that facilitates the exchange of GDP for GTP in the nucleotide-binding pocket of a GTP-binding protein. Typically this includes the small GTPases of the Rho and Ras families in signal transduction pathways.

Phenogram

A computer-generated diagram depicting taxonomic relationships among organisms based on similarity of particular characteristics. This is usually independent of evolutionary history and without reference to the significance of characteristics used to generate the diagram.

Extracellular matrix

The part of animal tissue outside of, and between, cells. It provides structural support to cells and also provides extracellular cues. It comprises many components, including connective tissue made up of components such as collagen or fibronectin that are the ligands for integrin receptors.

Focal adhesion

An integrin-mediated cell–extracellular matrix substrate adhesion structure that anchors the ends of actin filaments (stress fibres) and mediates strong attachments to substrates. It also comprises the sites where integrin extracellular matrix receptors cluster and initiate signalling.

Src homology 2 domain

(SH2 domain). A signalling protein docking module that generally recognizes and binds to Tyr-phosphorylated amino acid stretches in other proteins in a sequence-specific context. It is present in many signalling proteins and thereby has a key role in relaying cascades of signal transduction by bringing together protein complexes.

Src homology 3 domain

(SH3 domain). A protein module of about 50 amino acids that recognizes and binds to sequences that are typically rich in proline.

Fluorescence resonance energy transfer

(FRET). The non-radiative transfer of energy from a donor fluorophore to an acceptor fluorophore that is typically <80 Å away. FRET will only occur between fluorophores in which the emission spectrum of the donor has a significant overlap with the excitation of the acceptor. FRET is used as an 'in cell' read-out of protein proximity.

Epithelial to mesenchymal transition

The morphological change of an epithelial-like cell into a mesenchymal-like cell, which is often coincident with more migratory and invasive properties.

Lamellipodia

Broad, flat protrusions at the leading edge of a moving cell that are enriched with a branched network of actin filaments, which give rise to the force to push lamelliopdia forward at the leading edge of motile cells.

Nascent integrin adhesion

Clusters of ligand-bound integrins and their intracellular protein partners that form transiently when cells first probe and contact their extracellular matrix. Clusters that stabilize may be precursors of mature focal adhesions.

Pleckstrin homology domain

(PH domain). A protein module of 100 amino acids that is found in many signalling proteins and that generally binds to phospholipids. Different PH domains interact with various phospholipids and are therefore involved in the targeting of the proteins to membranous structures.

E3 ubiquitin ligase

The third enzyme in a series of enzymes that are responsible for ubiquitylation and often the subsequent targeting of modified proteins for proteosomal degradation. E3 enzymes, which are numerous, provide platforms for binding target substrates, thereby conferring specificity to the process of targeted degradation in cells.

Centrosome

A specialized organelle that duplicates during interphase and that constitutes the centre of the mitotic spindle.

Aptamer

A nucleic acid- or peptide-based sequence, either engineered or natural, that forms a precise three-dimensional structure that can selectively bind to a target molecule.

Filopodia

Thin, transient actin protrusions that extend out from the cell surface and are formed by the elongation of bundled actin filaments in its core.

Inside-out signalling

The process of inside-out signalling refers to signals from within the cell, usually mediated by cytoplasmic proteins, that can rapidly change ligand binding by cell surface receptors. This promotes conformational changes in the receptors themselves that often lead to their activation. This term is commonly used for the binding of ligands to extracellular matrix components.

Outside-in signalling

The transduction of information from the extracellular environment to the inside of cells via transmembrane receptors, such as integrins or growth factor receptors. This results in initiation of intracellular signalling in response to environmental cues.

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Frame, M., Patel, H., Serrels, B. et al. The FERM domain: organizing the structure and function of FAK. Nat Rev Mol Cell Biol 11, 802–814 (2010). https://doi.org/10.1038/nrm2996

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