Cited by 206Cell Adhesion Molecules ResearchCellular Mechanics and InteractionsProtein Kinase Regulation and GTPase Signaling

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FAK Structure and Regulation by Membrane Interactions and Force in Focal Adhesions

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Tapial Martínez, Paula, López Navajas, Pilar, Lietha, Daniel·2020·Biomolecules

DOI 10.3390/biom10020179PMC PMC7072507

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Abstract

Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase with key roles in the regulation of cell adhesion migration, proliferation and survival. In cancer FAK is a major driver of invasion and metastasis and its upregulation is associated with poor patient prognosis. FAK is autoinhibited in the cytosol, but activated upon localisation into a protein complex, known as focal adhesion complex. This complex forms upon cell adhesion to the extracellular matrix (ECM) at the cytoplasmic side of the plasma membrane at sites of ECM attachment. FAK is anchored to the complex via multiple sites, including direct interactions with specific membrane lipids and connector proteins that attach focal adhesions to the actin cytoskeleton. In migrating cells, the contraction of actomyosin stress fibres attached to the focal adhesion complex apply a force to the complex, which is likely transmitted to the FAK protein, causing stretching of the FAK molecule. In this review we discuss the current knowledge of the FAK structure and how specific structural features are involved in the regulation of FAK signalling. We focus on two major regulatory mechanisms known to contribute to FAK activation, namely interactions with membrane lipids and stretching forces applied to FAK, and discuss how they might induce structural changes that facilitate FAK activation.

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Figure 1 Structures of FAK domains. (a) Schematic domain structure of FAK. Domain boundaries and regulatory phosphorylation sites are indicated. (b) Crystal structure of the FAK FERM domain containing the F1, F1 and F3 lobes (PDB accession 2AL6). The 10 C-terminal residues integral to the FAK FERM domain, but not in ERM FERM domains, are coloured in orange. The linker is in yellow with the PxxP motif known to interact with the Src SH3 domain in red. The Y397 autophosphorylation site in the linker and the KAKTLRK motif in the F2 lobe (blue) are labelled. (c) Structure of the active FAK kinase domain with Y576 and Y577 in the activation loop (A-loop) phosphorylated (PDB accession 2J0L). The A-loop is coloured in green. A non-hydrolysable ATP analogue (AMP-PNP) and a Mg2+ ion (yellow sphere) are bound to the active site. (d) Structure of the FAT domain bound to the paxillin LD4 peptide (PDB accession 1OW7). The paxillin LD4 peptide is in olive green and the N-terminal FAT extension in tan. Helices H1-H4 and the S910 and Y925 phosphorylation sites are labelled. (e) Crystal structure of the FERM-kinase region of FAK in the autoinhibited conformation (PDB accession 2J0J). Colouring is as in panels (a,b). (f) FERM dimer mediated by W266 interactions in the F3 lobe as observed in various crystal structures (shown from PDB accession 2AEH).CC BY · PubMed Central

Figure 2 Model for FAK activation in focal adhesions mediated by membrane interactions and force. Left: FAK can form dimers via F3 lobe interactions involving W266. FAK dimer formation is likely promoted upon recruitment into focal adhesions by increased local concentration and potentially by paxillin-FAT interactions that synergise with FAT-FERM interactions to stabilise FAK dimers. Middle: FAK interacts with nearby PIP2 rich membranes via the KAKTLRK basic patch in the FERM F2 lobe. Increased avidity for PIP2 of FAK dimers might enhance membrane attachment. Membrane interactions induce conformational changes that allow simultaneous interactions of FERM and kinase domains to the membrane and expose the FERM-kinase linker for efficient autophosphorylation on Y397. Right: Src binds with its SH2 domain to the phosphorylated Y397 site and with the SH3 domain to the PxxP motif in the FERM-kinase linker. Stretching forces applied to FAK by contracting actomyosin fibres cause release of the FAK kinase domain from FERM and membrane interactions, exposing the activation loop for efficient phosphorylation by Src, resulting in FAK activation.CC BY · PubMed Central

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Molecular Mechanisms of Stress-Responsive Changes in Collagen and Elastin Networks in Skin
Aziz, J., Shezali, H., Radzi, Z., Yahya, N. A., Abu Kassim, N. H., Czernuszka, J., & Rahman, M. T. (2016) · Skin Pharmacology and Physiology · doi:10.1159/000447017 · Cited by 7,323
Matrix Crosslinking Forces Tumor Progression by Enhancing Integrin Signaling
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“Levental and colleagues [85] used a breast cancer mouse model to show that stiffening of the tumour stroma, induced by increased ECM crosslinking, results in activation of FAK which in turn causes a highly aggressive and invasive behaviour of tumour cells.”
Background
Reduced cell motility and enhanced focal adhesion contact formation in cells from FAK-deficient mice
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Integrin-mediated signal transduction linked to Ras pathway by GRB2 binding to focal adhesion kinase
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“In this scenario, force could be a trigger to release the N-terminal FAT helix resulting in exposure of Y925 for phosphorylation by Src. Phosphorylated Y925 is a docking site for the adaptor protein Grb2 [90], which on the one hand links FAK signalling to the Ras/MAPK signalling pathway but was also suggested to recru…”
Background
Nanoscale architecture of integrin-based cell adhesions
Kanchanawong, P., Shtengel, G. E., Pasapera, A. M., Ramko, E. B., Davidson, M. W., Hess, H. F., & Waterman, C. M. (2010) · Nature · doi:10.1038/nature09621 · Cited by 1,572 · cited 3×
“Super-resolution optical microscopy has defined a layered focal adhesion architecture with a signalling layer closest to the plasma membrane, a central force transduction layer and an actin regulatory layer, the site of actin attachment to the focal adhesion complex [24].”
BackgroundInfluential
Measuring mechanical tension across vinculin reveals regulation of focal adhesion dynamics
Grashoff, C., Hoffman, B. D., Brenner, M. D., Zhou, R., Parsons, M., Yang, M. T., McLean, M. A., Sligar, S. G., Chen, C. S., Ha, T., et al. (2010) · Nature · doi:10.1038/nature09198 · Cited by 1,549
Stretching Single Talin Rod Molecules Activates Vinculin Binding
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pp125FAK a structurally distinctive protein-tyrosine kinase associated with focal adhesions.
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FAK in cancer: mechanistic findings and clinical applications
Sulzmaier, F. J., Jean, C., & Schlaepfer, D. D. (2014) · Nature Reviews Cancer · doi:10.1038/nrc3792 · Cited by 1,381 · cited 2×
“The importance of FAK in cell motility is also reflected in disease where FAK plays major roles in tumour invasion and metastasis [11].”
Background
FAK integrates growth-factor and integrin signals to promote cell migration
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Items 101–200 of 206

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Smith, S. F., Brewer, D. S., Hurst, R., & Cooper, C. S. (2024) · Cancers · doi:10.3390/cancers16091717 · Cited by 9
“Phosphorylated FAK is associated with metastasis, and the metalloproteinases MMP-2 and MMP-9 have roles in degrading the extracellular matrix [77].”
Background
Myocardial Cytoskeletal Adaptations in Advanced Kidney Disease
Halim, A., Narayanan, G., Hato, T., Ho, L., Wan, D., Siedlecki, A. M., Rhee, E. P., Allegretti, A. S., Nigwekar, S. U., Zehnder, D., et al. (2022) · Journal of the American Heart Association · doi:10.1161/jaha.121.022991 · Cited by 9
“50,51 RNA-seq showed significant downregulation A , Expression of FAK mRNA is significantly upregulated in left ventricular tissues from patients undergoing hemodialysis, ex vivo.”
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“The focal adhesion targeting (FAT) domain acts as a scaffolding protein, which allows the protein to localize and stabilize within the cell due to its interactions with paxillin [1,21] (Figure 2B).”
Background
O-GlcNAcylation of Focal Adhesion Kinase Regulates Cell Adhesion, Migration, and Proliferation via the FAK/AKT Pathway
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“[57–59].”
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Zhang, X., Zhang, Q., Yu, M., Zhang, Y., He, T., Qiu, Z., Qiu, Y., & Wang, W. (2023) · Journal of Ethnopharmacology · doi:10.1016/j.jep.2023.117349 · Cited by 8
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“17 As a key executor of FAs signaling events, the activation and stabilization of FAK was ﬁnely tuned for driving cell migration.”
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He, Y., Gang, B., Zhang, M., et al. (2024) · International Immunopharmacology · doi:10.1016/j.intimp.2024.111535 · Cited by 8
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Wang, X., Li, X., Niu, L., Lv, F., Guo, T., Gao, Y., Ran, Y., Huang, W., & Wang, B. (2024) · Oncogene · doi:10.1038/s41388-024-03027-y · Cited by 9
“The major molecular functions of FAK are executed by the phosphorylated form of FAK, which is induced by rapid autophosphorylation at tyrosine 397, and this initial phosphorylation subsequently activates phosphorylation at other sites [10 – 12].”
DNA demethylase TET2-mediated reduction of HADHB expression contributes to cadmium-induced malignant progression of colorectal cancer
Li, L., Jiang, M., Wang, W., Cao, X., Ma, Q., Han, J., Liu, Z., Huang, Y., & Chen, Y. (2024) · Ecotoxicology and Environmental Safety · doi:10.1016/j.ecoenv.2024.116579 · Cited by 8
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“FAK was correlated to FAs turnover, regulating the recombination of cytoskeleton and lamellipodia [14].”
BackgroundInfluential
ATX/LPA axis regulates FAK activation, cell proliferation, apoptosis, and motility in human pancreatic cancer cells
Liao, Y., Liu, L., Yang, J., et al. (2022) · In Vitro Cellular & Developmental Biology - Animal · doi:10.1007/s11626-022-00660-3 · Cited by 8
“…integrins and growth factor signals stimulated phosphorylation at tyrosine 397 (Y397) in FAK that is particularly responsible for FAK efficient activation and providing high affinity binding site for FAK-interacting proteins, being referred to as scaffolding function (Tapial Martínez et al. 2020).”
Background
A novel selective FAK inhibitor E2 inhibits ovarian cancer metastasis and growth by inducing cytotoxic autophagy
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“FA is a linking complex consists of various proteins, including integrin, PKC, plectin, RACK1, and c-Src (109).”
Background
PDGFRB promotes dedifferentiation and pulmonary metastasis through rearrangement of cytoskeleton under hypoxic microenvironment in osteosarcoma
Xu, E., Huang, Z. Y., Zhu, K., Hu, J., Ma, X., Wang, Y., Zhu, J., & Zhang, C. (2024) · Cellular Signalling · doi:10.1016/j.cellsig.2024.111501 · Cited by 7
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“In various cell types, including platelets, PTK2 is known to accumulate in focal adhesion sites formed upon stretching forces [19,20].”
Background
Potential Focal Adhesion Kinase Inhibitors in Management of Cancer: Therapeutic Opportunities from Herbal Medicine
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“reorganized signals in cancer cells, thereby inducing malignant growth and metastasis [2,3].”
BackgroundInfluential
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“Phosphorylation also enables FAK in the active conformation to be available for sequential phosphorylation at the C-terminal region (Tyr925) [26].”
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“Building on our findings regarding actomyosin contractility, we focused on the role of miR-29a-3p in regulating FAs and the actin cytoskeleton, both of which are also critical for cellular migration [32].”
Background
The ubiquitin ligase RNF8 regulates Rho GTPases and promotes cytoskeletal changes and motility in triple‐negative breast cancer cells
Carvalho, B. P. D., Chern, Y., He, J., & Chan, C. (2020) · FEBS Letters · doi:10.1002/1873-3468.13999 · Cited by 6
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“42,43 We studied whether B[a]P induced an increase in the number of focal adhesions, which were analyzed by staining of cells with anti ‐ p ‐ FAK Ab.”
Background
c-Src-induced vascular malformations require localised matrix degradation at focal adhesions
Essebier, P., Schimmel, L., Yordanov, T. E., Keyser, M. S., Yu, A., Noordstra, I., Hill, B., Yap, A. S., Stehbens, S. J., Lagendijk, A. K., et al. (2024) · Journal of Cell Science · doi:10.1242/jcs.262101 · Cited by 5
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“…migration requires the anterior portion of cells to protrude and attach onto the substrate surface, which is mediated by proteins that form focal adhesions, including integrin [37], focal adhesion kinase (FAK, also known as PTK2) [38], paxillin (PXN) [39], talin (TLN) [40], and vinculin (VCL) [41].”
Background
Mechanotransduction in fibrosis: Mechanisms and treatment targets
Yeh, C., Chou, C. E. N., & Yang, K. (2021) · Current topics in membranes · doi:10.1016/bs.ctm.2021.07.004 · Cited by 4
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“Finally, the increase in cell density was paralleled by a gradual accumulation of E-cadherin (Figure 1E) [27,28].”
Background
Focal adhesion kinase acts on the PI3K/Akt/mTOR pathway to modulate wear particle-induced autophagy in macrophages
Tu, Y., Pan, B., Wu, X., Hu, X., Li, Q., Zhang, Z., Sheng, P., & Chen, W. (2025) · International Immunopharmacology · doi:10.1016/j.intimp.2025.115246 · Cited by 4
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Vinculin Identified as a Potential Biomarker in Hand-Arm Vibration Syndrome Based on iTRAQ and LC–MS/MS-Based Proteomic Analysis
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Two Transient Receptor Potential Channels at Focal Adhesions
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Correlative light and electron microscopy reveals fork-shaped structures at actin entry sites of focal adhesions
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The mechanism of L1 cell adhesion molecule interacting with protein tyrosine kinase 2 to regulate the focal adhesion kinase–growth factor receptor-bound protein 2–son of sevenless–rat sarcoma pathway in the identification and treatment of type I high-risk endometrial cancer
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H19 lncRNA in programming prenatal development and DOHaD due to maternal obesity
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“Effective migration requires the formation of focal adhesions through proteins such as integrins [83], focal adhesion kinase (FAK) [84], paxillin (PXN), and talin (TLN) [25], which link the extracellular matrix (ECM) to the actin cytoskeleton and allow cells to move directionally.”
Phytochemical analysis and impact of Citrus hystrix peel water extract on proliferation and migration of skin keratinocytes by activating FAK/Src/MAPK/Akt pathway
Moolsup, F., Tanasawet, S., Woonnoi, W., Daodee, S., Parhira, S., Chonpathompikunlert, P., Muneerungsee, N., Wongtawatchai, T., & Sukketsiri, W. (2023) · Journal of Herbal Medicine · doi:10.1016/j.hermed.2023.100699 · Cited by 4
Lidocaine inhibits migration of tenocytes by downregulating focal adhesion kinase and paxillin phosphorylation
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“26,27 When FAK is autophosphorylated at tyrosine 397, it recruits the SRC family to form a complex and phosphorylates FAK at tyrosines 576 and 577.”
Background
A novel role of IGFBP5 in the migration, invasion and spheroids formation induced by IGF-I and insulin in MCF-7 breast cancer cells
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Additional file 4 of m6A-mediated upregulation of LINC01003 regulates cell migration by targeting the CAV1/FAK signaling pathway in glioma
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Additional file 2 of ZDHHC5-mediated S-palmitoylation of FAK promotes its membrane localization and epithelial-mesenchymal transition in glioma
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Additional file 3 of m6A-mediated upregulation of LINC01003 regulates cell migration by targeting the CAV1/FAK signaling pathway in glioma
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Additional file 6 of m6A-mediated upregulation of LINC01003 regulates cell migration by targeting the CAV1/FAK signaling pathway in glioma
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Authors: Tapial Martínez, P., López Navajas, P., & Lietha, D.
Affiliations: Centro de Investigaciones Biológicas (CIB), Spanish National Research Council (CSIC), Cell Signalling and Adhesion Group, 28040 Madrid, Spain
Consejo Superior de Investigaciones Científicas (ES)
Corresponding author: Lietha, Daniel
ORCID: Lietha, Daniel
Venue: Biomolecules
Publisher: MDPI AG
Published: 2020-01-24
Volume: 10
Issue: 2
Pages: 179
ISSN: 2218-273X (ISSN-L)
DOI: 10.3390/biom10020179
PMC: PMC7072507
OpenAlex: W3002011373
Semantic Scholar: 3830912f29816d1795a68aeaa4e040c80c112f67
Cited by: 206
References: 95
Citations by year: 2026: 16 · 2025: 21 · 2024: 45 · 2023: 44 · 2022: 41 · 2021: 24 · 2020: 15
FWCI: 4.32
Type: journal article
Language: en
Open access: gold
dx.doi.org
Licence: cc-by
creativecommons.org/licenses/by/4.0/ (vor)
Locations: Biomolecules (publishedVersion, cc-by)
PubMed Central (publishedVersion, cc-by)
PubMed (publishedVersion)
DIGITAL.CSIC (Spanish National Research Council (CSIC)) (submittedVersion, cc-by)
DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders: Ministerio de Ciencia, Innovación y Universidades (RTI2018-099318-B-I00, RTI2018)
Ministerio de Asuntos Económicos y Transformación Digital, Gobierno de España (BFU2016-77665-R)
European Regional Development Fund (BFU2016, RTI2018, BFU2016-77665-R)
Agencia Estatal de Investigación
Topics: Health Sciences › Medicine › Immunology and Allergy › Cell Adhesion Molecules Research
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular Mechanics and Interactions
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
Keywords: focal adhesion kinase, focal adhesions, membrane lipid interactions, mechanical forces, FAK activation, non-receptor tyrosine kinase, cell adhesion, extracellular matrix, metastasis, actin cytoskeleton
MeSH terms: Cell Adhesion, Cell Movement, Humans, Membranes, Actin Cytoskeleton, Phosphorylation, Signal Transduction, Focal Adhesions, Mechanotransduction, Cellular, Focal Adhesion Kinase 1

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FAK Structure and Regulation by Membrane Interactions and Force in Focal Adhesions

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