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FAK Structure and Regulation by Membrane Interactions and Force in Focal Adhesions
Open accessAbstract
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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“The osteoclast cytoskeleton is made of filamentous structures that belong to one of four categories: polarized actin filaments; polarized microtubules; non-polarized intermediate filaments; or non-polarized septin filaments. The cytoskeleton fulfills essential functions including cell adhesion, migration, contractility, division, vesicular transport, and bone resorption [2,3,4,5,6].”
From Osteoclasts and Microgravity (2020) · cites this paper as [5]
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Cites
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“The clover-leaf assembly of the FAK FERM domain is overall very similar to the one seen in the ERM family members ezrin [36], radixin [37], and moesin [38], but different to the FERM domain of talin, which surprisingly is found to arrange its lobes in a linear arrangement [39].”
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Schiller, H. B., Friedel, C. C., Boulègue, C., & Fässler, R. (2011) · EMBO Reports · doi:10.1038/embor.2011.5 · Cited by 350 · cited 1×
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Austen, K., Ringer, P., Mehlich, A., Chrostek‐Grashoff, A., Kluger, C., Klingner, C., Sabass, B., Zent, R., Rief, M., & Grashoff, C. (2015) · Nature Cell Biology · doi:10.1038/ncb3268 · Cited by 348 · cited 1×
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“In agreement with such a scenario, vinculin is shown to move away from the membrane towards the actin regulatory layer during myosin II mediated focal adhesion maturation [87].”
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BackgroundA conserved protonation-dependent switch controls drug binding in the Abl kinase
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BackgroundTalin contains three actin-binding sites each of which is adjacent to a vinculin-binding site
Hemmings, L., Rees, D. J. G., Ohanian, V., Bolton, S. J., Gilmore, A. P., PATEL, B., Priddle, H., Trevithick, J. E., Hynes, R. O., & Critchley, D. R. (1996) · Journal of Cell Science · doi:10.1242/jcs.109.11.2715 · Cited by 260
Direct association of pp125FAK with paxillin, the focal adhesion-targeting mechanism of pp125FAK.
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BackgroundFAK promotes recruitment of talin to nascent adhesions to control cell motility
Lawson, C., Lim, S., Uryu, S. A., Chen, X. L., Calderwood, D., & Schlaepfer, D. D. (2012) · The Journal of Cell Biology · doi:10.1083/jcb.201108078 · Cited by 237
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Dissecting the molecular architecture of integrin adhesion sites by cryo-electron tomography
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BackgroundFocal adhesion kinase signaling in unexpected places
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BackgroundMammary epithelial-specific disruption of the focal adhesion kinase blocks mammary tumor progression
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“In mouse models, FAK is shown to be responsible for skin and breast cancer invasion as well as breast to lung metastasis [12,13].”
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“Cellular strain, applied to cells by stretching of an elastic substrate the cells are growing on, directly increases the force experienced in focal adhesions and is shown to cause increased FAK phosphorylation levels in different cellular systems [28,29].”
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“Further, plating of cells on substrates with different stiffness, where stiffer substrates allow the generation of higher forces in focal adhesions, shows that FAK activity increases on stiffer substrates [27].”
BackgroundSpatial and Temporal Regulation of Focal Adhesion Kinase Activity in Living Cells
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“FAK is a key component of the focal adhesion signalling layer and is shown to directly interact with membrane lipids [25,26].”
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“It contains two PxxP motives, site I (P712PKP) interacts with the SH3 domain of p130Cas [47] and site II (P874PKKPP) with the SH3 domains of the small GTPase activating proteins GRAF and ASAP [48,49].”
BackgroundFAK promotes recruitment of talin to nascent adhesions to control cell motility
Lawson, C., Lim, S., Uryu, S. A., Chen, X. L., Calderwood, D., & Schlaepfer, D. D. (2012) · The Journal of Cell Biology · doi:10.1083/jcb.2011080781963c · Cited by 170 · cited 2×
“To this end, in mouse embryo fibroblasts it was observed that FAK is efficiently autophosphorylated in nascent focal adhesions independent of force application [52].”
BackgroundEndothelial-cell FAK targeting sensitizes tumours to DNA-damaging therapy
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The Structure of the Talin Head Reveals a Novel Extended Conformation of the FERM Domain
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The Structural Basis of Localization and Signaling by the Focal Adhesion Targeting Domain
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“To this end, in one crystal structure the first helix in FAT is swapped between two neighbouring FAT molecules in the crystal [33].”
BackgroundThe Rap1-RIAM-talin axis of integrin activation and blood cell function
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“On the other hand, a high-affinity integrin state initiating ECM binding can be triggered by the binding of intracellular components, such as talin, kindlin, and RIAM [22,23].”
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“mediated FAK activation is shown to be promoted by the plasma membrane lipid phosphatidylinositol 4,5-bisphosphate (PIP2) [26].”
BackgroundInfluentialSelf-citationFAK dimerization controls its kinase‐dependent functions at focal adhesions
Brami‐Cherrier, K., Gervasi, N., Arsenieva, D., Walkiewicz, K. W., Boutterin, M., Ortega, Á., Leonard, P. G., Seantier, B., Gasmi, L., Bouceba, T., et al. (2014) · The EMBO Journal · doi:10.1002/embj.201386399 · Cited by 145 · cited 4×
“These structures have defined the mechanism of FAK autoinhibition in the cytosol [35] and identified a number of interactions, including a mode of recruitment into focal adhesions via paxillin [53,54] and FERM mediated dimerization important for activation [44].”
BackgroundInfluentialFAK activity sustains intrinsic and acquired ovarian cancer resistance to platinum chemotherapy
Diaz Osterman, C. J., Ozmadenci, D., Kleinschmidt, E. G., Taylor, K. N., Barrie, A. M., Jiang, S., Bean, L. M., Sulzmaier, F. J., Jean, C., Tancioni, I., et al. (2019) · eLife · doi:10.7554/elife.47327 · Cited by 145
Ciobănaşu, C., Faivre, B., & Clainche, C. L. (2014) · Nature Communications · doi:10.1038/ncomms4095 · Cited by 141 · cited 1×
“The stretching of talin is shown to reveal cryptic binding sites for vinculin, resulting in stabilization of the focal adhesion complex and a stronger attachment to actin [83,84].”
BackgroundCrystal Structure of the FERM Domain of Focal Adhesion Kinase
Ceccarelli, D. F. J., Song, H. K., Poy, F., Schaller, M. D., & Eck, M. J. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m509188200 · Cited by 139 · cited 4×
“Crystallised FERM domains contain most of the linker residues following the FERM domain (residues 362–399 or 362–405, [31]).”
BackgroundMethodInfluentialStructural and mechanistic insights into mechanoactivation of focal adhesion kinase
Bauer, M. S., Baumann, F., Daday, C., Redondo, P. N., Durner, E., Jobst, M. A., Milles, L. F., Mercadante, D., Pippig, D. A., Gaub, H. E., et al. (2019) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1820567116 · Cited by 139 · cited 2×
“Further, using atomic force microscopy (AFM) based single molecule force spectroscopy, it was shown that forces applied to FAK molecules via the KAKTLRK lipid binding site in the FERM domain and the C-terminus of the kinase domain (the FAT domain was not included in these studies) results in rupture of autoinhibitory…”
MethodSelf-citationChen, S.-Y., & Chen, H. (2006) · Molecular and Cellular Biology · doi:10.1128/mcb.02186-05 · Cited by 139 · cited 1×
“This sequence is implicated in a number of interactions, including in binding to phosphorylated tails of the Met receptor [43], phosphoinositide lipids [25,26] (see Section 3), and via an intramolecular interaction to the C-terminal FAT domain [44] (see Section 2.”
BackgroundMechanism of Focal Adhesion Kinase Mechanosensing
Zhou, J., Aponte-Santamaria, C. A., Sturm, S., Bullerjahn, J. T., Bronowska, A. K., & Gräter, F. (2015) · PLoS Computational Biology · doi:10.1371/journal.pcbi.1004593 · Cited by 134 · cited 1×
“In a separate study, atomistic molecular dynamics simulations were performed, starting from autoinhibited FAK bound via the KAKTLRK site to an explicit PIP2 containing membrane bilayer [89].”
MethodFERM Domain Interaction Promotes FAK Signaling
Dunty, J., Gabarra-Niecko, V., King, M. L., Ceccarelli, D. F. J., Eck, M. J., & Schaller, M. D. (2004) · Molecular and Cellular Biology · doi:10.1128/mcb.24.12.5353-5368.2004 · Cited by 120 · cited 2×
“FAK mutated in the KAKTLRK sequence or FAK in PIP5KIγ knockdown cells still localise to focal adhesions, indicating that membrane interactions do not significantly contribute to FAK localisation [26,42].”
BackgroundLim, S., Chen, X. L., Tomar, A., Miller, N. L. G., Yoo, J., & Schlaepfer, D. D. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.129999 · Cited by 118
Structure of the Active N-terminal Domain of Ezrin
Smith, W. J., Nassar, N. N., Bretscher, A. P., Cerione, R. A., & Karplus, P. A. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m210601200 · Cited by 110 · cited 1×
“The clover-leaf assembly of the FAK FERM domain is overall very similar to the one seen in the ERM family members ezrin [36], radixin [37], and moesin [38], but different to the FERM domain of talin, which surprisingly is found to arrange its lobes in a linear arrangement [39].”
BackgroundMolecular Recognition of Paxillin LD Motifs by the Focal Adhesion Targeting Domain
Hoellerer, M. K., Noble, M. E. M., Labesse, G., Campbell, I. D., Werner, J. M., & Arold, S. T. (2003) · Structure · doi:10.1016/j.str.2003.08.010 · Cited by 107 · cited 2×
“These structures have defined the mechanism of FAK autoinhibition in the cytosol [35] and identified a number of interactions, including a mode of recruitment into focal adhesions via paxillin [53,54] and FERM mediated dimerization important for activation [44].”
BackgroundHunger‐Glaser, I., Salazar, E. P., Sinnett‐Smith, J. W., & Rozengurt, E. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m210876200 · Cited by 107 · cited 3×
“Subsequent studies have provided evidence for the propensity for this helix to detach from the four-helix bundle [56,57] and promote C-terminal phosphorylations on Y861, Y925 and S910 [58,59].”
BackgroundGrant, B. D., & Adams, J. A. (1996) · Biochemistry · doi:10.1021/bi952144+ · Cited by 95 · cited 1×
“A likely explanation provides the study of Grant and Adams [79] showing that, in kinase/substrate complexes and if the enzyme/substrate ratio is close to one, phosphorylation rates are not determined by steady-state kinetics as seen in regular turnover kinetics.”
BackgroundGarces, C. A., Kurenova, E., Golubovskaya, V., et al. (2006) · Cancer Research · doi:10.1158/0008-5472.can-05-1661 · Cited by 84
Gao, G., Prutzman, K. C., King, M. L., Scheswohl, D. M., DeRose, E. F., London, R. E., Schaller, M. D., & Campbell, S. L. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m309808200 · Cited by 81 · cited 3×
“These structures have defined the mechanism of FAK autoinhibition in the cytosol [35] and identified a number of interactions, including a mode of recruitment into focal adhesions via paxillin [53,54] and FERM mediated dimerization important for activation [44].”
BackgroundDixon, R. D. S., Chen, Y., Ding, F., Khare, S. D., Prutzman, K. C., Schaller, M. D., Campbell, S. L., & Dokholyan, N. V. (2004) · Structure · doi:10.1016/j.str.2004.09.011 · Cited by 75 · cited 2×
“Subsequent studies have provided evidence for the propensity for this helix to detach from the four-helix bundle [56,57] and promote C-terminal phosphorylations on Y861, Y925 and S910 [58,59].”
BackgroundWu, J.-C., Chen, Y., Kuo, C.-T., et al. (2015) · Scientific Reports · doi:10.1038/srep18476 · Cited by 64 · cited 1×
“These interactions can contribute to Src activation and have been reported to recruit Src into focal adhesions [60].”
BackgroundPlaza-Menacho, I., Morandi, A., Mologni, L., Boender, P. J., Gambacorti-Passerini, C. B., Magee, A. I., Hofstra, R. M. W., Knowles, P. P., McDonald, N. Q., & Isacke, C. M. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.168500 · Cited by 63
Papusheva, E., de Queiroz, F. M., Dalous, J., et al. (2009) · Journal of Cell Science · doi:10.1242/jcs.028738 · Cited by 55 · cited 1×
“Possibly, membrane binding was also the primary cause for a FRET change in a cellular study that used a similar FRET sensor but found that the sensor did not require FAK activity or autophosphorylation for an optimal FRET response upon localisation into focal adhesions [65].”
BackgroundYoon, S.-O., Shin, S., Karreth, F. A., Buel, G. R., Jedrychowski, M. P., Plas, D. R., Dedhar, S., Gygi, S. P., Roux, P. P., Dephoure, N., et al. (2017) · Molecular Cell · doi:10.1016/j.molcel.2017.06.033 · Cited by 53
Prutzman, K. C., Gao, G., King, M. L., Iyer, V. V., Mueller, G. A., Schaller, M. D., & Campbell, S. L. (2004) · Structure · doi:10.1016/j.str.2004.02.028 · Cited by 42 · cited 3×
“Subsequent studies have provided evidence for the propensity for this helix to detach from the four-helix bundle [56,57] and promote C-terminal phosphorylations on Y861, Y925 and S910 [58,59].”
BackgroundWang, Q., More, S. K., Vomhof‐DeKrey, E. E., Golovko, M. Y., & Basson, M. D. (2019) · Scientific Reports · doi:10.1038/s41598-019-51183-z · Cited by 41
Fragment-based discovery of focal adhesion kinase inhibitors
Grädler, U., Bomke, J., Müsil, D., Dresing, V., Lehmann, M., Hölzemann, G., Greiner, H. E., Esdar, C., Krier, M., & Heinrich, T. (2013) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2013.07.050 · Cited by 40 · cited 1×
“Although a crystal structure of FAK in the “DFG-out” conformation exists bound to a type II inhibitor [45], it is not clear whether FAK adopts this conformation merely as a result of specific ligand interactions, or whether it might be part of a native regulation or catalytic cycle as proposed for other kinases includ…”
BackgroundKadaré, G., Gervasi, N., Brami‐Cherrier, K., Blockus, H., Messari, S. E., Arold, S. T., & Girault, J. (2014) · Journal of Biological Chemistry · doi:10.1074/jbc.m114.593632 · Cited by 38 · cited 5×
“To some extent this might promote dissociation of FAK from focal adhesions [58].”
BackgroundInfluentialMarlowe, T. A., Lenzo, F. L., Figel, S. A., et al. (2016) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-16-0366 · Cited by 38 · cited 1×
“In oncogenic settings, and particular upon application of FAK inhibitors, it was shown that growth factor receptors can directly phosphorylate Y397 in FAK, thereby sustaining FAK scaffolding functions via phospho-Y397 even if FAK is efficiently inhibited [64].”
BackgroundYuan, C., Gou, X., Deng, J., Dong, Z., Ye, P., & Hu, Z. (2018) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2018.04.185 · Cited by 34
Structural Insights How PIP2 Imposes Preferred Binding Orientations of FAK at Lipid Membranes
Herzog, F. A., Braun, L., Schoen, I., & Viola Vogel, B. (2017) · The Journal of Physical Chemistry B · doi:10.1021/acs.jpcb.6b09349 · Cited by 34 · cited 1×
“Coarse grain molecular dynamics simulations of autoinhibited FAK on a PIP2 membrane indicated that after membrane binding via the KAKTLRK sequence in the FERM domain the protein would rotate into two possible membrane bound states where FERM and kinase domains lie flat on the membrane with both domains bound to PIP2 […”
BackgroundZhou, Z., Feng, H., & Bai, Y. (2006) · Proteins Structure Function and Bioinformatics · doi:10.1002/prot.21107 · Cited by 30 · cited 2×
“Subsequent studies have provided evidence for the propensity for this helix to detach from the four-helix bundle [56,57] and promote C-terminal phosphorylations on Y861, Y925 and S910 [58,59].”
BackgroundD’Onofrio, P. M., Shabanzadeh, A. P., Choi, B., et al. (2019) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.18-25257 · Cited by 21
Marlowe, T. A., Dementiev, A., Figel, S. A., Rivera, A., Flavin, M. T., & Cance, W. G. (2019) · BMC Molecular and Cell Biology · doi:10.1186/s12860-019-0193-4 · Cited by 21 · cited 1×
“Linker residues immediately following the FERM domain (368–375), including a PxxP motif known to constitute a binding site for the Src SH3 domain, are seen in two crystal structures to interact with the FERM F3 lobe and in one FERM molecule with the cleft between the F1 and F3 lobe [31,41].”
BackgroundExpression of Focal Adhesion Proteins in the Developing Rat Kidney
Matsuura, S., Kondo, S., Suga, K., Kinoshita, Y., Urushihara, M., & Kagami, S. (2011) · Journal of Histochemistry & Cytochemistry · doi:10.1369/0022155411413929 · Cited by 16
Phospholipid binding to the FAK catalytic domain impacts function
Hall, J. E., & Schaller, M. D. (2017) · PLoS ONE · doi:10.1371/journal.pone.0172136 · Cited by 7 · cited 3×
“However, a second site on the kinase domain, that includes residues R508, K621 and K627, has recently been shown to also contribute to PIP2 binding [77].”
BackgroundInfluential
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Dual Role of Reactive Oxygen Species and their Application in Cancer Therapy
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“On the one hand, FAK can lead to focal adhesion, and actin stress fibers located on the inside of the cell membrane adhere to the focal adhesion spot [82].”
BackgroundRoles of focal adhesion proteins in skeleton and diseases
Chen, S., He, T., Zhong, Y., Chen, M., Yao, Q., Chen, D., Shao, Z., & Xiao, G. (2022) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2022.09.020 · Cited by 157
PROTAC’ing oncoproteins: targeted protein degradation for cancer therapy
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Progress in the Development of Small Molecular Inhibitors of Focal Adhesion Kinase (FAK)
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Metadata
- 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)
- 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
- 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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