Role of Intermediate Filaments in Cell Locomotion

Abstract

Cell locomotion is essential for diverse pathophysiological processes, including embryogenesis, immune responses, wound healing and cancer metastasis. Intermediate filaments (IFs) are resilient cytoskeleton components that provide structural support and mechanical protection. Accumulating evidence suggests that IFs are dynamic structures that function as a scaffold for signalling networks, which regulate cell locomotion, shape change and mechanical responses. The dynamics of IFs are regulated by posttranslational modifications, crosstalk with other cytoskeletons and association with cell adhesion complexes. IFs differentially regulate cell locomotion, depending on the particular IF protein, the cell type, the cellular context and the mode of cell migration. In general, vimentin filaments promote and keratin filaments inhibit cell locomotion. These cytoplasmic IFs regulate cell locomotion by modulating the localisation and activity of signalling molecules and influencing the stability of cell–cell and cell–substrate adhesion complexes. Nuclear lamin‐A represses cell locomotion by stiffening the nucleus.

Key Concepts

  • Intermediate filaments (IFs) constitute the resilient cytoskeleton that provides structural support and protects cells from external forces.
  • IFs function as a dynamic scaffold for signalling networks that regulate locomotion, shape change and mechanical responses.
  • Cytoplasmic IFs are linked to desmosomes and hemidesmosomes at cell adhesion sites and linker of nucleoskeleton and cytoskeleton (LINC) complexes on the nuclear membrane.
  • The reorganisation and dynamics of IFs are regulated by posttranslational modifications, crosstalk with other cytoskeletons and association with cell adhesion complexes.
  • IFs differentially regulate cell locomotion, depending on the particular IF protein, the cell type, the cellular context and the mode of cell migration.
  • Vimentin IFs generally promote cell locomotion by destabilising desmosomes, promoting focal adhesion maturation and affecting the activity of signalling molecules.
  • Keratin IFs generally repress cell locomotion by stabilising desmosomes and hemidesmosomes and affecting the localisation and activity of signalling molecules.
  • Nuclear lamin‐A represses cell locomotion by stiffening the nucleus.
  • Keratin IFs and Rho signalling are mutually regulated, providing a feedback mechanism during mechanical responses.

Keywords: intermediate filament; cytoskeleton; posttranslational modification; cell migration; hemidesmosome; desmosome; linker of nucleoskeleton and cytoskeleton (LINC) complex; focal adhesion; mechanosensing; Rho family

Figure 1. (a) Structure of an intermediate filament (IF) protein. An monomer IF has a common domain structure consisting of an N‐terminal head domain, a central rod domain and a C‐terminal tail domain. The rod domain comprises α‐helical segments (1A, 1B, 2A and 2B) and nonhelical short spacer sequences. The amino acid sequences of the rod domain are highly conserved among all IF proteins, but the head and tail domains differ considerably in size and sequence. (b) Assembly of IFs. Two monomers form a parallel coiled‐coil dimer; two dimers associate to form an antiparallel tetramer, which is the basic assembly unit; eight tetramers laterally assemble to form a unit‐length filament (ULF); ULFs anneal longitudinally to form nonpolar filaments, which then undergo radial compaction to form mature cytoplasmic IFs of ∼10‐nm diameter. Nuclear lamins are composed of tetrameric filaments of ∼3.5‐nm diameter.
Figure 2. Intermediate filament (IF)‐coupled adhesion complexes. (a) Location of IF‐coupled adhesion complexes in cells. (b) Schematic structure of desmosome. Desmosomes are formed at cell–cell adhesions of epithelia and cardiac muscle cells and anchor IFs to form a bridge between neighbouring cells. (c) Schematic structure of hemidesmosome. Hemidesmosomes mediate cell–extracellular matrix (ECM) adhesion of epithelial cells and anchor IFs to integrins. (d) Schematic structure of the linker of nucleoskeleton and cytoskeleton (LINC) complex. The LINC complex is located on the nuclear envelope and indirectly connects cytoplasmic IFs to nuclear lamins. BP230, bullous pemphigoid 230; CD151, clusters of differentiation 151; Nesprin‐3, nuclear envelope spectrin repeat protein 3 and Sun, Sad1 and UNC‐84.
Figure 3. Key effects of intermediate filaments (IFs) and IF‐coupled adhesion complexes on cell locomotion. (a) The cell locomotion cycle. (1) The lamellipodial membrane protrusion is extended towards the direction of cell movement. (2) The lamellipodium attachment to the substrate initiates the formation of focal adhesions and hemidesmosomes. (3) The focal adhesions anchor stress fibres, which generate contractile forces and promote traction of the cell body. (4) The tail detaches from the substrate and retracts to the cell body. (b) Typical effects of cytoplasmic and nuclear IFs on cell locomotion. Blue lines represent cytoplasmic IFs; orange lines and networks represent actin filaments and the dark blue dotted line represents nuclear lamins. Commentaries in red and dark blue letters indicate the positive and negative impacts on cell movement, respectively.
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References

Alam H, Gangadaran P, Bhate AV, et al. (2011) Loss of keratin 8 phosphorylation leads to increased tumor progression and correlates with clinico‐pathological parameters of OSCC patients. PLoS One 6 (11): e27767.

Bordeleau F, Galarneau L, Gilbert S, et al. (2010) Keratin 8/18 modulation of protein kinase C‐mediated integrin‐dependent adhesion and migration of liver epithelial cells. Molecular Biology of the Cell 21 (10): 1698–1713.

Bordeleau F, Myrand Lapierre ME, Sheng Y and Marceau N (2012) Keratin 8/18 regulation of cell stiffness‐extracellular matrix interplay through modulation of Rho‐mediated actin cytoskeleton dynamics. PLoS One 6 (7): e38780.

Burgstaller G, Gregor M, Winter L and Wiche G (2010) Keeping the vimentin network under control: cell‐matrix adhesion‐associated plectin 1f affects cell shape and polarity of fibroblasts. Molecular Biology of the Cell 21 (19): 3362–3375.

Busch T, Armacki M, Eiseler T, et al. (2012) Keratin 8 phosphorylation regulates keratin reorganization and migration of epithelial tumor cells. Journal of Cell Science 125 (9): 2148–2159.

Chaudhuri O, Koshy ST, Branco da Cunha C, et al. (2014) Extracellular matrix stiffness and composition jointly regulate the induction of malignant phenotypes in mammary epithelium. Nature Materials 13 (10): 970–978.

Chung BM, Rotty JD and Coulombe PA (2013) Networking galore: intermediate filaments and cell migration. Current Opinion in Cell Biology 25 (5): 600–612.

Coulombe PA and Wong P (2004) Cytoplasmic intermediate filaments revealed as dynamic and multipurpose scaffolds. Nature Cell Biology 6 (8): 699–706.

Dave JM, Kang H, Abbey CA, et al. (2013) Proteomic profiling of endothelial invasion revealed receptor for activated C kinase 1 (RACK1) complexed with vimentin to regulate focal adhesion kinase (FAK). Journal of Biological Chemistry 288 (42): 30720–30733.

Davidson PM, Denais C, Bakshi MC and Lammerding J (2014) Nuclear deformability constitutes a rate‐limiting step during cell migration in 3‐D environments. Cell and Molecular Bioengineering 7 (3): 293–306.

Denais CM, Gilbert RM, Isermann P, et al. (2016) Nuclear envelope rupture and repair during cancer cell migration. Science 352 (6283): 353–358.

Dupin I, Sakamoto Y and Etienne‐Manneville S (2011) Cytoplasmic intermediate filaments mediate actin‐driven positioning of the nucleus. Journal of Cell Science 124 (6): 865–872.

Fujiwara S, Ohashi K, Mashiko T, et al. (2016) Interplay between Solo and keratin filaments is crucial for mechanical force‐induced stress fiber reinforcement. Molecular Biology of the Cell 27 (6): 954–966.

Harada T, Swift J, Irianto J, et al. (2014) Nuclear lamin stiffness is a barrier to 3D migration, but softness can limit survival. Journal of Cell Biology 204 (5): 669–682.

Havel LS, Kline ER, Salgueiro AM and Marcus AI (2015) Vimentin regulates lung cancer cell adhesion through a VAV2‐Rac1 pathway to control focal adhesion kinase activity. Oncogene 34 (15): 1979–1990.

Helfand BT, Mendez MG, Murthy SNP, et al. (2011) Vimentin organization modulates the formation of lamellipodia. Molecular Biology of the Cell 22 (8): 1274–1289.

Hookway C, Ding L, Davidson MW, et al. (2015) Microtubule‐dependent transport and dynamics of vimentin intermediate filaments. Molecular Biology of the Cell 26 (9): 1675–1686.

Huber F, Boire A, López MP and Koenderink GH (2015) Cytoskeletal crosstalk: when three different personalities team up. Current Opinion in Cell Biology 32: 39–47.

Inagaki M, Nishi Y, Nishizawa K, et al. (1987) Site‐specific phosphorylation induces disassembly of vimentin filaments in vitro. Nature 328 (6131): 649–652.

Ivaska J, Vuoriluoto K, Huovinen T, et al. (2005) PKCε‐mediated phosphorylation of vimentin controls integrin recycling and motility. EMBO Journal 24 (22): 3834–3845.

Jaffe AB and Hall A (2005) Rho GTPases: biochemistry and biology. Annual Review of Cell and Developmental Biology 21: 247–269.

Kleinschmidt EG and Schlaepfer DD (2017) Focal adhesion kinase signaling in unexpected places. Current Opinion in Cell Biology 45: 24–30.

Kölsch A, Windoffer R and Leube RE (2009) Actin‐dependent dynamics of keratin filament precursors. Cell Motility and the Cytoskeleton 66 (11): 976–985.

Kölsch A, Windoffer R, Würflinger T, et al. (2010) The keratin‐filament cycle of assembly and disassembly. Journal of Cell Science 123 (13): 2266–2272.

Kröger C, Loschke F, Schwarz N, et al. (2013) Keratins control intercellular adhesion involving PKC‐α–mediated desmoplakin phosphorylation. Journal of Cell Biology 201 (5): 681–692.

Leduc C and Etienne‐Manneville S (2015) Intermediate filaments in cell migration and invasion: the unusual suspects. Current Opinion in Cell Biology 32: 102–112.

Leube RE, Moch M and Windoffer R (2015) Intermediate filaments and the regulation of focal adhesion. Current Opinion in Cell Biology 32: 13–20.

Liao J and Omary MB (1996) 14‐3‐3 proteins associate with phosphorylated simple epithelial keratins during cell cycle progression and act as a solubility cofactor. Journal of Cell Biology 133 (2): 345–357.

Long HA, Boczonadi V, McInroy L, et al. (2006) Periplakin‐dependent re‐organisation of keratin cytoskeleton and loss of collective migration in keratin‐8‐downregulated epithelial sheets. Journal of Cell Science 119 (24): 5147–5159.

Lowery J, Kuczmarski ER, Herrmann H and Goldman RD (2015) Intermediate filaments play a pivotal role in regulating cell architecture and function. Journal of Biological Chemistry 290 (28): 17145–17153.

Lynch CD, Lazar AM, Iskratsch T, et al. (2013) Endoplasmic spreading requires coalescence of vimentin intermediate filaments at force‐bearing adhesions. Molecular Biology of the Cell 24 (1): 21–30.

Mendez MG, Kojima SI and Goldman RD (2010) Vimentin induces changes in cell shape, motility, and adhesion during the epithelial to mesenchymal transition. FASEB Journal 24 (6): 1838–1851.

Morgan JT, Pfeiffer ER, Thirkill TL, et al. (2011) Nesprin‐3 regulates endothelial cell morphology, perinuclear cytoskeletal architecture, and flow‐induced polarization. Molecular Biology of the Cell 22 (22): 4324–4334.

Nöding B, Herrmann H and Köster S (2014) Direct observation of subunit exchange along mature vimentin intermediate filaments. Biophysical Journal 107 (12): 2923–2931.

Omary MB (2009) “IF‐pathies”: a broad spectrum of intermediate filament‐associated diseases. Journal of Clinical Investigation 119 (7): 1756–1762.

Pajerowski JD, Dahl KN, Zhong FL, et al. (2007) Physical plasticity of the nucleus in stem cell differentiation. Proceedings of the National Academy of Sciences of the United States of America 104 (40): 15619–15624.

Peter M, Nakagawa J, Dorée M, et al. (1990) In vitro disassembly of the nuclear lamina and M phase‐specific phosphorylation of lamins by cdc2 kinase. Cell 61 (4): 591–602.

Peter A and Stick R (2015) Evolutionary aspects in intermediate filament proteins. Current Opinion in Cell Biology 32: 48–55.

Rabinovitz I, Toker A and Mercurio AM (1999) Protein kinase C‐dependent mobilization of the α6β4 integrin from hemidesmosomes and its association with actin‐rich cell protrusions drive the chemotactic migration of carcinoma cells. Journal of Cell Biology 146 (5): 1147–1159.

Robert A, Hookway C and Gelfand VI (2016) Intermediate filament dynamics: what we can see now and why it matters. Bioessays 38 (3): 232–243.

Roberts BJ, Pashaj A, Johnson KR and Wahl JK III (2011) Desmosome dynamics in migrating epithelial cells requires the actin cytoskeleton. Experimental Cell Research 317 (20): 2814–2822.

Rotty JD and Coulombe PA (2012) A wound‐induced keratin inhibits Src activity during keratinocyte migration and tissue repair. Journal of Cell Biology 197 (3): 381–389.

Seltmann K, Cheng F, Wiche G, et al. (2015) Keratins stabilize hemidesmosomes through regulation of β4‐integrin turnover. Journal of Investigative Dermatology 135 (6): 1609–1620.

Snider NT, Park H and Omary MB (2013) A conserved rod domain phosphotyrosine that is targeted by the phosphatase PTP1B promotes keratin 8 protein insolubility and filament organization. Journal of Biological Chemistry 288 (43): 31329–31337.

Snider NT and Omary MB (2014) Post‐translational modifications of intermediate filament proteins: mechanisms and functions. Nature Reviews Molecular Cell Biology 15 (3): 163–177.

Svitkina TM, Verkhovsky AB and Borisy GG (1996) Plectin sidearms mediate interaction of intermediate filaments with microtubules and other components of the cytoskeleton. Journal of Cell Biology 135 (4): 991–1007.

Turgay Y, Eibauer M, Goldman A, et al. (2017) The molecular architecture of lamins in somatic cells. Nature 543 (7644): 261–264.

Weber GF, Bjerke MA and DeSimone DW (2012) A mechanoresponsive cadherin‐keratin complex directs polarized protrusive behavior and collective cell migration. Developmental Cell 22 (1): 104–115.

Windoffer R, Kölsch A, Wöll S and Leube RE (2006) Focal adhesions are hotspots for keratin filament precursor formation. Journal of Cell Biology 173 (3): 341–348.

Wöll S, Windoffer R and Leube RE (2005) Dissection of keratin dynamics: different contributions of the actin and microtubule systems. European Journal of Cell Biology 84 (2–3): 311–328.

Further Reading

Goto H and Inagaki M (2014) New insights into roles of intermediate filament phosphorylation and progeria pathogenesis. IUBMB Life 66 (3): 195–200.

Izawa I and Inagaki M (2006) Regulatory mechanisms and functions of intermediate filaments: a study using site‐ and phosphorylation state‐specific antibodies. Cancer Science 97 (3): 167–174.

Ohashi K, Fujiwara S and Mizuno K (2017) Roles of the cytoskeleton, cell adhesion and rho signalling in mechanosensing and mechanotransduction. Journal of Biochemistry 161 (3): 245–254.

Vandebergh W and Bossuyt F (2012) Radiation and functional diversification of alpha keratins during early vertebrate evolution. Molecular Biology and Evolution 29 (3): 995–1004.

Wickstead B and Gull K (2011) The evolution of the cytoskeleton. Journal of Cell Biology 194 (4): 513–525.

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Fujiwara, Sachiko, and Mizuno, Kensaku(Jul 2017) Role of Intermediate Filaments in Cell Locomotion. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0026365]