Focal adhesion kinase: in command and control of cell motility

Key Points

  • In 1992, focal adhesion kinase (FAK) was identified as a substrate for viral Src and as a highly tyrosine-phosphorylated protein that localized to cell adhesion sites known as focal contacts. Since then, FAK has been shown to have a key role in both normal and tumour cell migration downstream of growth factor- and integrin- receptors. It is the formation of a FAK–Src signalling complex that is an initial and important event required for maximal FAK activation and cell migration.

  • FAK can be activated through intermolecular and intramolecular mechanisms, and tyrosine-phosphorylated FAK promotes interactions with various Src-homology (SH)2- and SH3-containing proteins. These proteins allow FAK activation to be connected to several signalling pathways such as the extracellular signal-regulated kinase 2 (ERK2)/mitogen-activated protein kinase (MAPK) cascade and small GTPases such as Rac and Rho. Phosphorylation of the C-terminal domain of FAK might control its localization to focal contacts by altering the binding of paxillin.

  • FAK functions as a signalling-protein scaffold for the assembly and subsequent maturation of focal contacts. FAK–Src kinase activity contributes to these events by promoting signalling that leads to the phosphorylation of phosphatidylinositol lipids. FAK–Src also functions to promote the disassembly of focal contacts, in part by activating intracellular proteases such as calpain and extracellular matrix metalloproteinases. New findings also link FAK–Src signalling to the regulation of cadherin-mediated cell–cell contacts.

  • In cell protrusions of migrating cells, coordinated changes in actin and microtubule structures are regulated by FAK signalling to Rho-family GTPases. FAK binds to and can phosphorylate GTPase-activating proteins (GAPs) and guanine nucleotide-exchange factors (GEFs) for Rho, and neuronal Wiskott–Aldrich syndrome protein (N-WASP), and can exert control over actin crosslinking by phosphorylating α-actinin.

  • The receptor-proximal position of FAK facilitates its role as an integrator of biochemical signals and mechanical forces that are experienced by moving cells. It is in this unique signalling position that FAK can regulate cytoskeletal or cell adhesion site dynamics and thereby control cell motility.

Abstract

A central question in cell biology is how membrane-spanning receptors transmit extracellular signals inside cells to modulate cell adhesion and motility. Focal adhesion kinase (FAK) is a crucial signalling component that is activated by numerous stimuli and functions as a biosensor or integrator to control cell motility. Through multifaceted and diverse molecular connections, FAK can influence the cytoskeleton, structures of cell adhesion sites and membrane protrusions to regulate cell movement.

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Figure 1: Focal adhesion kinase integrates signals to promote cell migration.
Figure 2: Focal adhesion kinase domain structure and phosphorylation sites.
Figure 3: Focal adhesion kinase (FAK)–Src signals that regulate cell motility and focal contact localization.
Figure 4: Focal adhesion kinase promotes cytoskeletal fluidity.
Figure 5: Focal adhesion kinase influences phospholipid and microtubule structures.

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Acknowledgements

S. Mitra is supported by a fellowship from the California Tobacco-Related Disease Research Program and D. Schlaepfer is supported by grants from the National Cancer Institute. This is manuscript 16827-IMM from The Scripps Research Institute.

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Correspondence to David D. Schlaepfer.

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DATABASES

Entrez Gene

PTK2

Swiss-Prot

calpain

CDK5

Diaphanous

E-cadherin

ezrin

FAK

FIP200

Fyn

N-cadherin

N-WASP

p130Cas

paxillin

PTPα

RhoA

SHP2

Src

talin

TRIO

Yes

FURTHER INFORMATION

The Schlaepfer laboratory

Glossary

INTEGRINS

A large family of heterodimeric transmembrane proteins that function as receptors for cell-adhesion molecules.

EXTRACELLULAR MATRIX

(ECM). The complex, multi-molecular material that surrounds cells. The ECM comprises a scaffold on which tissues are organized, it provides cellular microenvironments and it regulates various cellular functions.

RHO-FAMILY GTPases

A subfamily of small (21 kDa) GTP-binding proteins that are related to Ras and that regulate the cytoskeleton. The nucleotide-bound state is regulated by GTPase-activating proteins, which catalyse hydrolysis of the bound GTP, and guanine nucleotide-exchange factors, which catalyse GDP–GTP exchange.

STRESS FIBRES

Also termed 'actin-microfilament bundles', these are bundles of parallel filaments that contain F-actin and other contractile molecules, and often stretch between cell attachments as if under stress.

LAMELLIPODIA

Broad, flat protrusions at the leading edge of a moving cell that are enriched with a branched network of actin filaments.

HeLa CELLS

An established tissue-culture strain of human epidermoid carcinoma cells, containing 70–80 chromosomes per cell. These cells were originally derived from tissue taken from a patient named Henrietta Lacks in 1951.

ADAPTOR PROTEINS

Proteins that augment cellular responses by recruiting other proteins to a complex. They usually contain several protein–protein interaction domains.

G-PROTEIN-COUPLED RECEPTOR

A seven-helix membrane-spanning cell-surface receptor that signals through heterotrimeric GTP-binding and GTP-hydrolysing G-proteins to stimulate or inhibit the activity of a downstream enzyme.

SRC-HOMOLOGY (SH)3-DOMAIN

A protein sequence of 50 amino acids that recognizes and binds sequences that are rich in proline.

GTPase-ACTIVATING PROTEIN

(GAP). A protein that stimulates the intrinsic ability of a GTPase to hydrolyse GTP to GDP. Therefore, GAPs negatively regulate GTPases by converting them from active (GTP-bound) to inactive (GDP-bound).

AUTOPHOSPHORYLATION

The transfer of a phosphate group by a protein kinase either to a residue in the same kinase molecule (cis) or to a residue in a different kinase molecule but of the same type (trans).

SH2 DOMAIN

A protein motif that recognizes and binds tyrosine-phosphorylated sequences, and thereby has a key role in relaying cascades of signal transduction.

SRC-FAMILY KINASES

Kinases that belong to the Src family of tyrosine kinases, the largest of the non-receptor-tyrosine-kinase families.

MARGINAL ZONE

A region in the spleen in which white blood cell precursors such as B-cells, granulocytes, macrophages and plasma-cells reside or transit through during primary or secondary immune responses.

ACTIVATION LOOP

A conserved structural motif in kinase domains, which needs to be phosphorylated for full activation of the kinase.

GUANINE NUCLEOTIDE-EXCHANGE FACTOR

A protein that facilitates the exchange of GDP for GTP in the nucleotide-binding pocket of a GTP-binding protein.

MEMBRANE RUFFLE

A process that is formed by the movement of lamellipodia that are in the dynamic process of folding back onto the cell body from which they previously extended.

LD MOTIF

A short sequence found within proteins that has the consensus sequence LDXLLXXL and functions as a protein-binding interface.

MATRIX METALLOPROTEINASES

Proteolytic enzymes that degrade the extracellular matrix and have important roles in tissue remodelling and tumour metastasis.

LEADING EDGE

The thin margin of a lamellipodium that spans the area of the cell from the plasma membrane to a depth of about 1 μm into the lamellipodium.

ARP2/3 COMPLEX

A complex that consists of two actin-related proteins ARP2 and ARP3, along with five smaller proteins. When activated, the ARP2/3 complex binds to the side of an existing actin filament and nucleates the assembly of a new actin filament. The resulting branch structure is Y-shaped.

GANGLIOSIDE

An anionic glycosphingolipid that carries, in addition to other sugar residues, one or more sialic acid residues.

LIPID RAFTS

Lateral aggregates of cholesterol and sphingomyelin that are thought to occur in the plasma membrane.

ADHERENS JUNCTION

A cell–cell adhesion complex that contains classical cadherins and catenins that are attached to cytoplasmic actin filaments.

TIGHT JUNCTION

A circumferential ring at the apex of epithelial cells that seals adjacent cells to one another. Tight junctions regulate solute and ion flux between adjacent epithelial cells.

DOMINANT NEGATIVE

A defective protein that retains interaction capabilities and so competes with normal proteins, thereby impairing protein function.

TANGENTIAL FLUID SHEAR STRESS

A planar force exerted by the friction of a flowing substance — for example, forces experienced by endothelial cells as blood flows through capillaries.

CYTOTROPHOBLAST

The inner trophoblastic layer of cells that give rise to the syncytiotrophoblast facing the maternal circulation and constitute a layer through which all substances must pass from the mother to the fetus.

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Mitra, S., Hanson, D. & Schlaepfer, D. Focal adhesion kinase: in command and control of cell motility. Nat Rev Mol Cell Biol 6, 56–68 (2005). https://doi.org/10.1038/nrm1549

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