In cell biology, focal adhesions (also cell–matrix adhesions or FAs) are large macromolecular assemblies through which mechanical force and regulatory signals are transmitted between the extracellular matrix (ECM) and an interacting cell. More precisely, focal adhesions are the sub-cellular structures that mediate the regulatory effects (i.e., signaling events) of a cell in response to ECM adhesion.[1]
Immunofluorescence coloration of actin (green) and the focal adhesion protein vinculin (red) in a fibroblast. Focal adhesions are visible as red dots at the end of the green bundles.
Focal adhesions serve as the mechanical linkages to the ECM, and as a biochemical signaling hub to concentrate and direct numerous signaling proteins at sites of integrin binding and clustering.
Focal adhesions are integrin-containing, multi-protein structures that form mechanical links between intracellular actin bundles and the extracellular substrate in many cell types. Focal adhesions are large, dynamic protein complexes through which the cytoskeleton of a cell connects to the ECM. They are limited to clearly defined ranges of the cell, at which the plasma membrane closes to within 15 nm of the ECM substrate.[2] Focal adhesions are in a state of constant flux: proteins associate and disassociate with it continually as signals are transmitted to other parts of the cell, relating to anything from cell motility to cell cycle. Focal adhesions can contain over 100 different proteins, which suggests a considerable functional diversity.[3] More than anchoring the cell, they function as signal carriers (sensors), which inform the cell about the condition of the ECM and thus affect their behavior.[4] In sessile cells, focal adhesions are quite stable under normal conditions, while in moving cells their stability is diminished: this is because in motile cells, focal adhesions are being constantly assembled and disassembled as the cell establishes new contacts at the leading edge, and breaks old contacts at the trailing edge of the cell. One example of their important role is in the immune system, in which white blood cells migrate along the connective endothelium following cellular signals to damaged biological tissue.
Morphology
Connection between focal adhesions and proteins of the extracellular matrix generally involves integrins. Integrins bind to extra-cellular proteins via short amino acid sequences, such as the RGD motif (found in proteins such as fibronectin, laminin, or vitronectin), or the DGEA and GFOGER motifs found in collagen. Integrins are heterodimers which are formed from one beta and one alpha subunit. These subunits are present in different forms, their corresponding ligands classify these receptors into four groups: RGD receptors, laminin receptors, leukocyte-specific receptors and collagen receptors. Within the cell, the intracellular domain of integrin binds to the cytoskeleton via adapter proteins such as talin, α-actinin, filamin, vinculin and tensin. Many other intracellular signalling proteins, such as focal adhesion kinase, bind to and associate with this integrin-adapter protein–cytoskeleton complex, and this forms the basis of a focal adhesion.
Adhesion dynamics with migrating cells
The dynamic assembly and disassembly of focal adhesions plays a central role in cell migration. During cell migration, both the composition and the morphology of the focal adhesion change. Initially, small (0.25μm²) focal adhesions called focal complexes (FXs) are formed at the leading edge of the cell in lamellipodia: they consist of integrin, and some of the adapter proteins, such as talin, paxillin and tensin. Many of these focal complexes fail to mature and are disassembled as the lamellipodia withdraw. However, some focal complexes mature into larger and stable focal adhesions, and recruit many more proteins such as zyxin. Recruitment of components to the focal adhesion occurs in an ordered, sequential manner.[5] Once in place, a focal adhesion remains stationary with respect to the extracellular matrix, and the cell uses this as an anchor on which it can push or pull itself over the ECM. As the cell progresses along its chosen path, a given focal adhesion moves closer and closer to the trailing edge of the cell. At the trailing edge of the cell the focal adhesion must be dissolved. The mechanism of this is poorly understood and is probably instigated by a variety of different methods depending on the circumstances of the cell. One possibility is that the calcium-dependent protease calpain is involved: it has been shown that the inhibition of calpain leads to the inhibition of focal adhesion-ECM separation. Focal adhesion components are amongst the known calpain substrates, and it is possible that calpain degrades these components to aid in focal adhesion disassembly[6]
Actin retrograde flow
The assembly of nascent focal adhesions is highly dependent on the process of retrograde actin flow. This is the phenomenon in a migrating cell where actin filaments polymerize at the leading edge and flow back towards the cell body. This is the source of traction required for migration; the focal adhesion acts as a molecular clutch when it tethers to the ECM and impedes the retrograde movement of actin, thus generating the pulling (traction) force at the site of the adhesion that is necessary for the cell to move forward. This traction can be visualized with traction force microscopy. A common metaphor to explain actin retrograde flow is a large number of people being washed downriver, and as they do so, some of them hang on to rocks and branches along the bank to stop their downriver motion. Thus, a pulling force is generated onto the rock or branch that they are hanging on to. These forces are necessary for the successful assembly, growth, and maturation of focal adhesions.[7]
Natural biomechanical sensor
Extracellular mechanical forces, which are exerted through focal adhesions, can activate Src kinase and stimulate the growth of the adhesions. This indicates that focal adhesions may function as mechanical sensors, and suggests that force generated from myosin fibers could contribute to maturing the focal complexes.[8] This gains further support from the fact that inhibition of myosin-generated forces leads to slow disassembly of focal adhesions, by changing the turnover kinetics of the focal adhesion proteins.[9]
The relationship between forces on focal adhesions and their compositional maturation, however, remains unclear. For instance, preventing focal adhesion maturation by inhibiting myosin activity or stress fiber assembly does not prevent forces sustained by focal adhesions, nor does it prevent cells from migrating.[10][11] Thus force propagation through focal adhesions may not be sensed directly by cells at all time and force scales.
Their role in mechanosensing is important for durotaxis.
^Chen, CS; Alonso, JL; Ostuni, E; Whitesides, GM; Ingber, DE (2003). "Cell shape provides global control of focal adhesion assembly". Biochemical and Biophysical Research Communications. 307 (2): 355–61. doi:10.1016/s0006-291x(03)01165-3. PMID 12859964.
^Zaidel-Bar, R; Cohen, M; Addadi, L; Geiger, B (2004). "Hierarchical assembly of cell matrix adhesion complexes". Biochemical Society Transactions. 32 (3): 416–20. CiteSeerX10.1.1.624.3354. doi:10.1042/bst0320416. PMID 15157150.
^Zamir, E; Geiger, B (2001). "Molecular complexity and dynamics of cell–matrix adhesions". Journal of Cell Science. 114 (20): 3583–90. doi:10.1242/jcs.114.20.3583. PMID 11707510.
^Riveline, D; Zamir, E; Balaban, NQ; Schwarz, US; Ishizaki, T; Narumiya, S; Kam, Z; Geiger, B; Bershadsky, AD (2001). "Focal contacts as mechanosensors: externally applied local mechanical force induces growth of focal contacts by an mDia1-dependent and ROCK-independent mechanism". Journal of Cell Biology. 153 (6): 1175–86. doi:10.1083/jcb.153.6.1175. PMC2192034. PMID 11402062.
^Zaidel-Bar, R; Cohen, M; Addadi, L; Geiger, B (June 2004). "Hierarchical assembly of cell-matrix adhesion complexes". Biochemical Society Transactions. 32 (Pt3): 416–20. CiteSeerX10.1.1.624.3354. doi:10.1042/bst0320416. PMID 15157150.
^Huttenlocher, A; Palecek, SP; Lu, Q; Zhang, W; Mellgren, RL; Lauffenburger, DA; Ginsberg, MH; Horwitz, AF (1997). "Regulation of cell migration by the calcium-dependent protease calpain". Journal of Biological Chemistry. 272 (52): 32719–22. doi:10.1074/jbc.272.52.32719. PMID 9407041.
^Gardel, M. L.; Sabass, B.; Ji, L.; Danuser, G.; Schwarz, U. S.; Waterman, C. M. (8 December 2008). "Traction stress in focal adhesions correlates biphasically with actin retrograde flow speed". The Journal of Cell Biology. 183 (6): 999–1005. doi:10.1083/jcb.200810060. PMC2600750. PMID 19075110.
^Wolfenson, H.; Bershadsky, A.; Henis, Y. I.; Geiger, B. (2011). "Actomyosin-generated tension controls the molecular kinetics of focal adhesions". J Cell Sci. 124 (9): 1425–32. doi:10.1242/jcs.077388. PMC3078811. PMID 21486952.
^Beningo, Karen A.; Dembo, Micah; Kaverina, Irina; Small, J. Victor; Wang, Yu-li (2001-05-14). "Nascent Focal Adhesions Are Responsible for the Generation of Strong Propulsive Forces in Migrating Fibroblasts". The Journal of Cell Biology. 153 (4): 881–888. doi:10.1083/jcb.153.4.881. ISSN 0021-9525. PMC2192381. PMID 11352946.
^Stricker, Jonathan; Aratyn-Schaus, Yvonne; Oakes, Patrick W.; Gardel, Margaret L. (2011-06-22). "Spatiotemporal constraints on the force-dependent growth of focal adhesions". Biophysical Journal. 100 (12): 2883–2893. Bibcode:2011BpJ...100.2883S. doi:10.1016/j.bpj.2011.05.023. ISSN 1542-0086. PMC3123981. PMID 21689521.
External links
MBInfo - Focal Adhesion
MBInfo - Focal Adhesion Assembly
MBInfo - Regulation of Focal Adhesion Assembly
AdhesomeFAnetwork 2022-07-31 at the Wayback Machine Database with all known focal adhesion proteins and their biochemical interactions
Intercellular Connections
Zaidel-Bar Cell Adhesion Lab
March 08, 2023
focal, adhesion, cell, biology, focal, adhesions, also, cell, matrix, adhesions, large, macromolecular, assemblies, through, which, mechanical, force, regulatory, signals, transmitted, between, extracellular, matrix, interacting, cell, more, precisely, focal, . In cell biology focal adhesions also cell matrix adhesions or FAs are large macromolecular assemblies through which mechanical force and regulatory signals are transmitted between the extracellular matrix ECM and an interacting cell More precisely focal adhesions are the sub cellular structures that mediate the regulatory effects i e signaling events of a cell in response to ECM adhesion 1 Immunofluorescence coloration of actin green and the focal adhesion protein vinculin red in a fibroblast Focal adhesions are visible as red dots at the end of the green bundles Focal adhesions serve as the mechanical linkages to the ECM and as a biochemical signaling hub to concentrate and direct numerous signaling proteins at sites of integrin binding and clustering Contents 1 Structure and function 2 Morphology 3 Adhesion dynamics with migrating cells 3 1 Actin retrograde flow 3 2 Natural biomechanical sensor 4 See also 5 References 6 External linksStructure and function EditFocal adhesions are integrin containing multi protein structures that form mechanical links between intracellular actin bundles and the extracellular substrate in many cell types Focal adhesions are large dynamic protein complexes through which the cytoskeleton of a cell connects to the ECM They are limited to clearly defined ranges of the cell at which the plasma membrane closes to within 15 nm of the ECM substrate 2 Focal adhesions are in a state of constant flux proteins associate and disassociate with it continually as signals are transmitted to other parts of the cell relating to anything from cell motility to cell cycle Focal adhesions can contain over 100 different proteins which suggests a considerable functional diversity 3 More than anchoring the cell they function as signal carriers sensors which inform the cell about the condition of the ECM and thus affect their behavior 4 In sessile cells focal adhesions are quite stable under normal conditions while in moving cells their stability is diminished this is because in motile cells focal adhesions are being constantly assembled and disassembled as the cell establishes new contacts at the leading edge and breaks old contacts at the trailing edge of the cell One example of their important role is in the immune system in which white blood cells migrate along the connective endothelium following cellular signals to damaged biological tissue Morphology EditConnection between focal adhesions and proteins of the extracellular matrix generally involves integrins Integrins bind to extra cellular proteins via short amino acid sequences such as the RGD motif found in proteins such as fibronectin laminin or vitronectin or the DGEA and GFOGER motifs found in collagen Integrins are heterodimers which are formed from one beta and one alpha subunit These subunits are present in different forms their corresponding ligands classify these receptors into four groups RGD receptors laminin receptors leukocyte specific receptors and collagen receptors Within the cell the intracellular domain of integrin binds to the cytoskeleton via adapter proteins such as talin a actinin filamin vinculin and tensin Many other intracellular signalling proteins such as focal adhesion kinase bind to and associate with this integrin adapter protein cytoskeleton complex and this forms the basis of a focal adhesion Adhesion dynamics with migrating cells EditThe dynamic assembly and disassembly of focal adhesions plays a central role in cell migration During cell migration both the composition and the morphology of the focal adhesion change Initially small 0 25mm focal adhesions called focal complexes FXs are formed at the leading edge of the cell in lamellipodia they consist of integrin and some of the adapter proteins such as talin paxillin and tensin Many of these focal complexes fail to mature and are disassembled as the lamellipodia withdraw However some focal complexes mature into larger and stable focal adhesions and recruit many more proteins such as zyxin Recruitment of components to the focal adhesion occurs in an ordered sequential manner 5 Once in place a focal adhesion remains stationary with respect to the extracellular matrix and the cell uses this as an anchor on which it can push or pull itself over the ECM As the cell progresses along its chosen path a given focal adhesion moves closer and closer to the trailing edge of the cell At the trailing edge of the cell the focal adhesion must be dissolved The mechanism of this is poorly understood and is probably instigated by a variety of different methods depending on the circumstances of the cell One possibility is that the calcium dependent protease calpain is involved it has been shown that the inhibition of calpain leads to the inhibition of focal adhesion ECM separation Focal adhesion components are amongst the known calpain substrates and it is possible that calpain degrades these components to aid in focal adhesion disassembly 6 Actin retrograde flow Edit The assembly of nascent focal adhesions is highly dependent on the process of retrograde actin flow This is the phenomenon in a migrating cell where actin filaments polymerize at the leading edge and flow back towards the cell body This is the source of traction required for migration the focal adhesion acts as a molecular clutch when it tethers to the ECM and impedes the retrograde movement of actin thus generating the pulling traction force at the site of the adhesion that is necessary for the cell to move forward This traction can be visualized with traction force microscopy A common metaphor to explain actin retrograde flow is a large number of people being washed downriver and as they do so some of them hang on to rocks and branches along the bank to stop their downriver motion Thus a pulling force is generated onto the rock or branch that they are hanging on to These forces are necessary for the successful assembly growth and maturation of focal adhesions 7 Natural biomechanical sensor Edit Extracellular mechanical forces which are exerted through focal adhesions can activate Src kinase and stimulate the growth of the adhesions This indicates that focal adhesions may function as mechanical sensors and suggests that force generated from myosin fibers could contribute to maturing the focal complexes 8 This gains further support from the fact that inhibition of myosin generated forces leads to slow disassembly of focal adhesions by changing the turnover kinetics of the focal adhesion proteins 9 The relationship between forces on focal adhesions and their compositional maturation however remains unclear For instance preventing focal adhesion maturation by inhibiting myosin activity or stress fiber assembly does not prevent forces sustained by focal adhesions nor does it prevent cells from migrating 10 11 Thus force propagation through focal adhesions may not be sensed directly by cells at all time and force scales Their role in mechanosensing is important for durotaxis See also EditActin TES protein PaxillinReferences Edit Chen CS Alonso JL Ostuni E Whitesides GM Ingber DE 2003 Cell shape provides global control of focal adhesion assembly Biochemical and Biophysical Research Communications 307 2 355 61 doi 10 1016 s0006 291x 03 01165 3 PMID 12859964 Zaidel Bar R Cohen M Addadi L Geiger B 2004 Hierarchical assembly of cell matrix adhesion complexes Biochemical Society Transactions 32 3 416 20 CiteSeerX 10 1 1 624 3354 doi 10 1042 bst0320416 PMID 15157150 Zamir E Geiger B 2001 Molecular complexity and dynamics of cell matrix adhesions Journal of Cell Science 114 20 3583 90 doi 10 1242 jcs 114 20 3583 PMID 11707510 Riveline D Zamir E Balaban NQ Schwarz US Ishizaki T Narumiya S Kam Z Geiger B Bershadsky AD 2001 Focal contacts as mechanosensors externally applied local mechanical force induces growth of focal contacts by an mDia1 dependent and ROCK independent mechanism Journal of Cell Biology 153 6 1175 86 doi 10 1083 jcb 153 6 1175 PMC 2192034 PMID 11402062 Zaidel Bar R Cohen M Addadi L Geiger B June 2004 Hierarchical assembly of cell matrix adhesion complexes Biochemical Society Transactions 32 Pt3 416 20 CiteSeerX 10 1 1 624 3354 doi 10 1042 bst0320416 PMID 15157150 Huttenlocher A Palecek SP Lu Q Zhang W Mellgren RL Lauffenburger DA Ginsberg MH Horwitz AF 1997 Regulation of cell migration by the calcium dependent protease calpain Journal of Biological Chemistry 272 52 32719 22 doi 10 1074 jbc 272 52 32719 PMID 9407041 Gardel M L Sabass B Ji L Danuser G Schwarz U S Waterman C M 8 December 2008 Traction stress in focal adhesions correlates biphasically with actin retrograde flow speed The Journal of Cell Biology 183 6 999 1005 doi 10 1083 jcb 200810060 PMC 2600750 PMID 19075110 Wang Y Botvinick EL Zhao Y Berns MW Usami S Tsien RY Chien S 2005 Visualizing the mechanical activation of Src Nature 434 7036 1040 5 Bibcode 2005Natur 434 1040W doi 10 1038 nature03469 PMID 15846350 S2CID 4429147 Wolfenson H Bershadsky A Henis Y I Geiger B 2011 Actomyosin generated tension controls the molecular kinetics of focal adhesions J Cell Sci 124 9 1425 32 doi 10 1242 jcs 077388 PMC 3078811 PMID 21486952 Beningo Karen A Dembo Micah Kaverina Irina Small J Victor Wang Yu li 2001 05 14 Nascent Focal Adhesions Are Responsible for the Generation of Strong Propulsive Forces in Migrating Fibroblasts The Journal of Cell Biology 153 4 881 888 doi 10 1083 jcb 153 4 881 ISSN 0021 9525 PMC 2192381 PMID 11352946 Stricker Jonathan Aratyn Schaus Yvonne Oakes Patrick W Gardel Margaret L 2011 06 22 Spatiotemporal constraints on the force dependent growth of focal adhesions Biophysical Journal 100 12 2883 2893 Bibcode 2011BpJ 100 2883S doi 10 1016 j bpj 2011 05 023 ISSN 1542 0086 PMC 3123981 PMID 21689521 External links EditMBInfo Focal Adhesion MBInfo Focal Adhesion Assembly MBInfo Regulation of Focal Adhesion Assembly AdhesomeFAnetwork Archived 2022 07 31 at the Wayback Machine Database with all known focal adhesion proteins and their biochemical interactions Intercellular Connections Zaidel Bar Cell Adhesion Lab Retrieved from https en wikipedia org w index php title Focal adhesion amp oldid 1123633125, wikipedia, wiki, book, books, library,
