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Cortactin

Page updated 8/10/02

Cortactin is present as a p80 and p85 Kda protein in many cell types.  The protein was first identified as being a major substrate of the tyrosine kinase pp60src (Wu & Parsons, 1991). The main structural feature of the protein is that at the N-terminus there are five and a half 37-aminoacid repeats, these appear to be responsible for the actin-binding.  This repeat region occupies about a third of the protein.  The repeat region is followed by a helical region and then a proline rich region and finally at the C-terminus, an SH3 domain (Fig 1).  The proline rich domain is thought to bind the SH2 domain of v-src (Okamura & Resh, 1995) the viral version of the normal c-src known to phosphorylate cortactin.  Cortactin bundles microfilaments and this bundling is inhibited by tyrosine phosphorylation (Huang et al, 1997b).  One pathway that activates the pathway leading to tyrosine phosphorylation of cortactin results from a cell adhesion molecule in brain micro-vessel endothelial cells (Durieu-Trautmann et al, 1994, another is the growth factor (Zhan et al, 1993), but presumably the very many mechanisms for pp60src activation would also result in cortactin phosphorylation and subsequent loss of actin binding. 

    The association between cortactin and actin seems to be quite tight (Kd = 0.43mm) (Wu & Parsons, 1993), however if the protein is a dimer, then of course this means that the actual actin binding region binds with considerably less affinity. It is presently unclear whether cortactin bundles microfilaments through multiple ABP within the 5.5 repeat region or whither the protein dimerises.

Cortactin Binding Proteins

Perhaps the activity and or localisation of cortactin is modulated by a cortactin binding protein that binds through cortactin's SH3 domain  (Du et al, 1998).  This protein known as CortBP1A or Shank 2 is part of a larger family of proteins, the Shank family of scaffold proteins (Sheng & Kim, 2000), these gather together several structural and signalling proteins at excitatory synapse.  A different cortactin binding protein () has been found by a others (Ohoka & Takai, 1998).  Recently cortactin has been discovered to bind the Arp2/3 complex (Weed et al, 2000; McNiven, et al, 2000).  HS1, a cortactin paralog expressed in cells of the haematopoietic lineage and cortactin its self binds to Hax-1 which in turn binds the polycystic kidney protein PKD2 (Gallagher et al, 2000).  The potassium channel Kv1.2 also binds to cortactin (Hattan et al, 2002). This interaction is reversed by the tyrosine phosphorylation of the C-terminus of the channel.  Kv1.2 and cortactin are localised to the leading edge of moving cells (Hattan et al, 2002). 

   The role of Cortactin in Differentiation.

Several studies indicate that cortactin is involved in the switching and maintenance of various states of differentiation. Anti-sense mediated reduction in cortactin expression for example (Cheng et al, 2000) switched neurons to a GABAergic phenotype. 

Other Related Web-sites:-

  Cortactin-GFP dynamics in living cells  (Kaksonen et al, 2000)
  

References:-

Fawaz, F.S., van Ooij, C., Homola, E., Mutka, S.C. & Engel, J.N. (1997). "Infection with Chlamydia trachomatis alters the tyrosine phosphorylation and/or localization of several host cell proteins including cortactin.  Infect. & Immunity 65(12), 5301-5308.

Durieu-Trautmann, O., Chaverot, N., Cazaubon, S., Strosberg, A.D. & Couraud, P.-O. (1994). "Intercellular adhesion molecule 1 activation induces tyrosine phosphorylation of the cytoskeleton-associated protein cortactin in brain microvessel endothelial cells." J.Biol.Chem. 269(17), 12536-12540.

Du, Y., Weed, S.A., Xiong, W.C., Marshall, W.C., & Parsons, J.T. (1998). “Identification of a novel cortactin SH3 domain binding protein and its localization to growth cones of cultured neurons.” Mol.Cell.Biol. 18(10), 5838-5851.

Gallagher AR. Cedzich A. Gretz N. Somlo S. Witzgall R (2000). "The polycystic kidney disease protein PKD2 interacts with Hax-1, a protein associated with the actin cytoskeleton." PNAS 97(8), 4017-4022.

Hattan, D., Nesti, E., Cachero, T. G. & Morielli, A. D. (2002) Tyrosine Phosphorylation of Kv1.2 Modulates Its Interaction with the Actin-binding Protein Cortactin, J. Biol. Chem. 277, 38596-38606.

Huang, C., Tandon, N.N., Greco, N.J., Ni, Y., Wang, T. & Zhan, X. (1997a). "Proteolysis of platelet cortactin by calpain." J.Biol.Chem. 272(31) 19248-19252.

Huang, C., Ni, Y., Wang, T., Gao, Y., Haudenschild, C.C. & Zhan, X. (1997b). "Down-regulation of the filamentous actin cross-linking activity of cortactin by Src-mediated tyrosine phosphorylation." J.Biol.Chem. 272(21) 13911-13915.

Kaksonen, M., Peng, H.B. & Rauvala, H. (2000). "Association of cortactin with dynamic actin in lamellipodia and on endosomal vesicles." J.Cell Sci. 113, 4421-4426.

McNiven, M.A., Kim, L., Krueger, E.W., Orth, J.D., Cao, H., & Wong, T.W. (2000). "Regulation interactions between dynamin and the actin-binding protein cortactin modulate cell shape." J.Cell Biol. 151(1), 187-198.

Ohoka, Y. & Takai, Y. (1998). "Isolation and characterization of cortactin isoforms and a novel cortactin-binding protein, CBP90." Genes to Cells. 3, 603-612

Okamura, H., & Resh, M.D. (1995). "p80/85 cortactin associates with the Src SH2 domain and colocalizes with v-Src in transformed cells." J.Biol.Chem. 270, 26613-26618.

Sheng, M. & Kim, E. (2000). "The Shank family of scaffold proteins". J.Cell Sci. 113, 1851-1856.

Weed, S.A., Karginov, A.V., Schafer, D.A., Weaver, A.M., Kinley, A.W., Cooper, J.A. & Parsons, J.T. (2000). "Cortactin localization to sites of actin assembly in lamellipodia requires interactions with F-actin and the Arp2/3 complex." J.Cell Biol. 152(1), 29-40.

Wu , H., Reynolds, A.B., Kanner, S.B., Vines, R.R. & Parsons, J.T. (1991). "Identification of a novel cytoskeleton-associated pp60src substrate. Mol.Cell Biol. 11, 5113-5124.

Wu, H. & Parsons, J.T. (1993). "Cortactin, an 80/85-kilodalton pp60src substrate, is a filamentous actin-binding protein enriched in the cell cortex." J.Cell Biol. 120, 1417-1426.

Zhan, X., Hu, X., Hampton, B., Burgess, W.H., Friesel, R. and Macaig, T. (1993). "Murine cortactin is phosphorylated in response to fibroblast growth factor-1 on tyrosine residues late in the G1 pase of the BALB/c 3T3 cell cycle." J.Biol.Chem. 268(32), 24427-24431

 
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