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The role of focal-adhesion kinase in cancer — a new therapeutic opportunity

Key Points

  • Focal-adhesion kinase (FAK) is a non-receptor tyrosine kinase that provides signalling and scaffolding functions at sites of integrin adhesion. It is involved in the regulation of turnover of these adhesion sites, a process that is crucial in the control of cell migration.

  • FAK is linked to the protection of cells from anoikis (suspension-induced cell death). This anti-apoptotic function is potentially linked to the ability of FAK to sequester receptor-interacting protein (RIP) from the death-receptor machinery.

  • Substantial circumstantial evidence has accumulated linking overexpression of FAK to a wide range of human epithelial cancers. Levels of FAK expression correlate with the invasive potential of tumours.

  • Using a mouse model of skin carcinogenesis, a direct requirement for FAK has now been shown during tumour progression in vivo. These observations are probably linked to the ability of FAK to protect cells from apoptosis.

  • Inhibition of FAK function might provide an attractive anticancer target, however it is not yet clear what the most effective strategy would be. Potential intervention routes are inhibition of the kinase activity of FAK or disruption of crucial protein–protein interactions.

Abstract

Focal-adhesion kinase (FAK) is an important mediator of growth-factor signalling, cell proliferation, cell survival and cell migration. Given that the development of malignancy is often associated with perturbations in these processes, it is not surprising that FAK activity is altered in cancer cells. Mouse models have shown that FAK is involved in tumour formation and progression, and other studies showing that FAK expression is increased in human tumours make FAK a potentially important new therapeutic target.

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Figure 1: Focal-adhesion kinase as a signal integrator.
Figure 2: Focal-adhesion kinase tyrosine phosphorylation regulates downstream signalling events.
Figure 3: Focal-adhesion kinase influences cell migration by molecular signalling pathways.
Figure 4: Focal-adhesion kinase influences cell migration through additional molecular signalling pathways.
Figure 5: Expression of focal-adhesion kinase during tumour progression in the mouse skin carcinogenesis model.
Figure 6: Model of the possible contributions of focal-adhesion kinase in cancer development.

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Acknowledgements

The authors would like to dedicate this review to Valerie Fincham, who died on 23 February 2005. Val worked on Rous sarcoma virus, the regulation and functions of v-Src, and on FAK in our laboratory for many years. Each of us benefited enormously from her talents and her dedication to her research and the laboratory effort. We also acknowledge other members of Research Group 1 at the Beatson Institute (BICR) for their work on FAK, and John Wyke for commenting on the manuscript. We would also like to thank Allan Balmain for advice and cell lines quoted here, and Stephen Bell, Maria Hendry and Tom Hamilton from BICR Services for all their help.

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Correspondence to Margaret C. Frame.

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DATABASES

Entrez Gene

CDC42

CRK

DOCK180

E-cadherin

FAK

GRB2

MMP2

p53

RAC1

RHOA

RIP

SRC

TGFβ

National Cancer Institute

cervical cancer

colon cancer

head and neck cancer

ovarian cancer

prostate cancer

rectal cancer

thyroid cancer

Glossary

HAPTOTACTIC MIGRATION

Migration of cells towards fixed attractants to which the cells bind. Often used to describe movement of cells towards extracellular-matrix components mediated by binding to specific integrins.

3D MATRIX

Reconstituted cell growth matrix such as Matrigel or fibrillar collagen, which is designed to mimic the in vivo environment encountered by tumour cells and so provide a surrogate when they are invading in vitro. This allows monitoring of cancer cells in culture migrating through a 3D matrix environment.

CYTOTROPHOBLAST

Part of the mammalian placenta; that is, the inner cellular layer of the trophectoderm (trophoblast), between the syncitiotrophoblast and chorionic villus capillaries.

DEATH-RECEPTOR COMPLEX

A multiprotein complex involved in the cellular response to pro-apoptotic stimuli. It links cell-surface receptors to the intracellular signalling cascade that accompanies programmed cell death.

DMBA/TPA MOUSE SKIN CARCINOGENESIS MODEL

Two-stage chemical carcinogenesis model that progresses from normal skin to benign papillomas to invasive tumours through several well-characterized stages. An initial treatment with DMBA serves as the tumour initiator followed by treatment with TPA as the promoter during tumour formation.

INDUCIBLE Cre–LOX SYSTEM

Method for the introduction of genetic modifications into specific genes by homologous recombination using Cre, a site-specific bacteriophage-P1-derived recombinase. The Cre recombinase cuts at the LOXP-tagged genes.

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McLean, G., Carragher, N., Avizienyte, E. et al. The role of focal-adhesion kinase in cancer — a new therapeutic opportunity. Nat Rev Cancer 5, 505–515 (2005). https://doi.org/10.1038/nrc1647

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