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 =
(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.
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.
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)
neurons to a GABAergic phenotype.
F.S., van Ooij, C., Homola, E., Mutka, S.C. & Engel, J.N. (1997).
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Hattan, D., Nesti, E., Cachero, T. G. &
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isoforms and a novel cortactin-binding protein, CBP90." Genes to Cells.
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domain and colocalizes with v-Src in transformed cells." J.Biol.Chem.
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S.A., Karginov, A.V., Schafer, D.A., Weaver, A.M., Kinley, A.W., Cooper, J.A.
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