For a cell to move, it must adhere to a sub­strate and exert trac­tion. Adhe­sion occurs at spe­cific foci at which the actin cytoskele­ton on the inside of the cell is linked via trans­mem­brane recep­tors (inte­grins) to the extra­cel­lu­lar matrix on the out­side. These adhe­sion sites are com­posed of com­plexes of more than 50 dif­fer­ent pro­teins (Geiger et al., 2009), includ­ing struc­tural, sig­nal­ing and adap­tor mol­e­cules:

Highly sim­pli­fied schematic illus­tra­tion of the organ­i­sa­tion of a focal adhe­sion. Trans­mem­brane inte­grins (alpha/beta) bind to matrix lig­ands on the out­side of the cell, and to a com­plex of mol­e­cules inside the cell that link to actin fil­a­ments. At focal adhe­sions, the actin fil­a­ments are bun­dled by actin fil­a­ment cross-linkers, includ­ing the con­trac­tile pro­tein myosin. Ten­sion in the bun­dle, gen­er­ated by myosin, is required to main­tain the clus­ter­ing of inte­grins and the integrity of focal adhe­sions (Bur­ridge and Chrzanowska-Wodnicka, 1996).

Adhe­sion foci can be visu­alised in liv­ing cells by tag­ging sin­gle pro­teins belong­ing to the adhe­sion com­plex with a flu­o­res­cent probe. The adhe­sion sites are ini­ti­ated under lamel­lipo­dia and filopo­dia as focal com­plexes (see fig­ure in Rho-GTPases). Focal com­plexes can either form and dis­solve, with a life­time of around 12mins, or can per­sist and dif­fer­en­ti­ate into larger focal adhe­sions (see Rho-GTPases). Exam­ples of this dif­fer­en­ti­a­tion from focal com­plexes to focal adhe­sions is shown in the videos of the next two fig­ures. Focal com­plexes and focal adhe­sions formed at the advanc­ing cell front remain sta­tion­ary, rel­a­tive to the sub­strate.

The for­ma­tion of sub­strate adhe­sion sites in a migrat­ing gold­fish fibrob­last. The cell was trans­fected with GFP-actin (green) and microin­jected with rhodamine-tagged vin­culin (an adhe­sion com­po­nent; red). The pro­trud­ing cell front is marked by a dif­fuse band of actin fil­a­ments (the lamel­lipodium), which con­tains radial fil­a­ment bun­dles (filopo­dia) that project beyond the cell edge. Dif­fer­ent types of adhe­sion foci (red) can be dis­tigu­ished: small foci in asso­ci­a­tion with lamel­lipo­dia and filopo­dia (focal com­plexes) and, behind the lamel­lipodium, larger foci asso­ci­ated with actin fil­a­ment bun­dles (focal adhe­sions). Focal adhe­sions are also observed at the periph­ery of retract­ing cell edges (bot­tom region of fig­ure). Focal com­plexes and focal adhe­sions in the advanc­ing front remain sta­tion­ary, rel­a­tive to the sub­strate, whereas, focal adhe­sions at the retract­ing edges can slide. (Video was pro­duced by Olga Krylyshk­ina: from Small et al., 2002).

A highly enlarged detail of the video in the fig­ure above, show­ing the orig­i­na­tion of adhe­sion foci (focal com­plexes) in asso­ci­a­tion with lamel­lipo­dia and filopo­dia.

Devel­op­ment of early adhe­sion sites under­neath filopo­dia in a fish fibrob­last trans­fected with mCherry-actin (red) and GFP-paxillin (another adhe­sion pro­tein; green). (Nemethova et al, JCB 2008)

If pro­tru­sion of a front ceases, the cell edge retracts to the level of the out­er­most focal adhe­sions. Fur­ther retrac­tion results in the slid­ing and even­tual detach­ment of these adhe­sion sites. This is the sce­nario at the rear and flanks of a migrat­ing cell (Rid et al., 2005):

Fish fibrob­last trans­fected with GFP-zyxin, show­ing slid­ing focal adhe­sions

Dif­fer­ent cell types use dif­fer­ent adhe­sion strate­gies to move. The faster mov­ing cell types show a higher pro­por­tion of focal com­plexes as com­pared to focal adhe­sions. Exam­ples of alter­na­tive adhe­sion strate­gies are shown for a mouse melanoma cell and for a fish ker­a­to­cyte in the fol­low­ing fig­ures:

Adhe­sion dynam­ics at the rapidly migrat­ing front of a B16 mouse melanoma cell mov­ing on laminin. The cell was trans­fected with GFP-VASP, which is recruited to adhe­sion foci, as well as to the very tip of advanc­ing lamel­lipo­dia. Focal com­plexes are formed behind the cell front that turnover within 1-2mins. Very few develop into focal adhe­sions (see top right at sta­tion­ary cell edge). (Rot­tner et al., 1999)

Adhe­sion dynam­ics in a migrat­ing fish ker­a­to­cyte. Short-lived focal com­plexes form under the advanc­ing lamel­lipodium. Larger, slid­ing adhe­sions, sim­i­lar to focal adhe­sions, are formed at retract­ing edges. These lat­ter adhe­sions are how­ever short-lived, since the cell tra­verses its own length within 23 mins. Video cour­tesy of Kurt Ander­son (Ander­son and Cross, 2000).

Related Pub­li­ca­tions

  • Ander­son, K. I., Cross, R. (2000). Con­tact dynam­ics dur­ing ker­a­to­cyte motil­ity. Curr. Biol. 10, 253260. NCBI PubMed
  • Bur­ridge, K., Chrzanowska-Wodnicka,  M. (1996). Focal adhe­sions, con­trac­til­ity, and sig­nal­ing. Annu Rev Cell Dev Biol. 12, 463518. NCBI PubMed
  • Geiger, B., Spatz, J. P., Ber­shad­sky A. D. (2009). Envi­ron­men­tal sens­ing through focal adhe­sions. Nat Rev Mol Cell Biol. 10, 121133. NCBI PubMed
  • Nemethova, M., Auinger, S., Small, J. V. (2008). Build­ing the actin cytoskele­ton: filopo­dia con­tribute to the con­struc­tion of con­trac­tile bun­dles in the lamella. J Cell Biol. 180, 12331244. PDF
  • Rid R., Schiefer­meier N., Grig­oriev I., Small J. V., Kave­rina I. (2005). The last but not the least: the ori­gin and sig­nif­i­cance of trail­ing adhe­sions in fibrob­las­tic cells. Cell Motil Cytoskele­ton. 61, 16171. PDF
  • Rot­tner, K., Behrendt, B., Small, J. V., Wehland, J. (1999). VASP dynam­ics dur­ing lamel­lipo­dia pro­tru­sion. Nat. Cell. Biol. 1, 321322. PDF
  • Small, J.V., Geiger, B., Kave­rina, I., Ber­shad­sky, A. (2002). How do micro­tubules guide migrat­ing cells? Nat. Rev. Mol. Cell Biol. 3, 95764. PDF

Related Web­sites