David Critchley's Research Interests

Integrins are the principal family of adhesion receptors mediating cellular interactions with the extracellular matrix (ECM). As such, they support a wide variety of processes which are dependent on cell-ECM interactions including cell proliferation, the suppression of apoptosis and cell migration, all of which are important in embryonic development and in tissue homeostasis in the adult.


The role of the cytoskeletal protein talin in integrin-mediated cell adhesion


Cell adhesion to the extracellular matrix is fundamental to the development of multi-cellular organisms, and involves the coordinated assembly and disassembly of the integrin family of cell adhesion molecules into complexes containing cytoplasmic proteins with linker, scaffolding, adaptor, regulatory and mechano transduction functions. Studies at the cellular and organismal level show that the cytoskeletal protein talin plays a pivotal role in this regard. Thus, talin promotes integrin clustering as well as switching integrins from a low to high affinity state, although this also requires the kindlin family of proteins. Talin also provides a direct link between integrins and the actin cytoskeleton, and acts as a scaffold for the recruitment of other proteins such as vinculin, which is known to be important for stabilizing integrin-containing cell matrix junctions (focal adhesions; FAs). 

There are two talin genes in vertebrates, and both talin1 and talin2 (~270kDa; 2541 amino acids) are comprised of a globular N-terminal head (~50kDa) and a large flexible C-terminal rod (~220kDa). The talin head contains a FERM domain made up of F1, F2 and F3 domains, but is atypical in that F1 contains a large unstructured loop, and is preceded by an additional domain (F0) with homology to F1. As a result, the talin FERM domain adopts a more extended conformation than other FERM domains. The talin F3 FERM domain binds the cytoplasmic domains of β-integrin subunits and the hyaluronan receptor layilin, as well as the C-terminal region of PIPKIγ90, a splice variant of phosphatidylinositol(4) phosphate-5-kinase type Iγ which regulates the assembly of FAs. The talin rod consists of ~62 helices that are organized into a series of amphipathic helical bundles, followed by a single C-terminal helix responsible for talin dimerisation. It contains an integrin-binding site, at least two actin-binding sites the best characterised of which is at the C-terminus, and multiple binding sites for vinculin, which itself has numerous binding partners including F-actin. The reader is referred to the following  articles and reviews on talin:

(i) Goult BT, Zacharchenko T, Bate N, Tsang R, Hey F, Gingras AR, Elliott PR, Roberts GC, Ballestrem C, Critchley DR, Barsukov IL. (2013) RIAM and vinculin binding to talin are mutually exclusive and regulate adhesion assembly and turnover. J Biol Chem. 288(12):8238-49.

(ii) Critchley DR (2009) Biochemical and structural properties of the integrin-associated cytoskeletal protein talin. Annu Rev Biophys 38: 235-254.

(iii) Calderwood DA, Campbell, ID and Critchley DR. (2013) Talins and kindlins: partners in integrin-mediated adhesion. Nature Rev Mol Cell Biol 14(8) : 503-517

Talin domain structure and ligand binding sites


Talin domain structure updated.png 

Isoform-specific Talin Monoclonal Antibodies

Monoclonal antibodies specific for talin1 or talin2 are described in:

Praekelt, U., et al. (2012). "New isoform-specific monoclonal antibodies reveal different sub-cellular localisations for talin1 and talin2." Eur J Cell Biol 91(3): 180-191.

Debrand, E., et al. (2012). "Mice carrying a complete deletion of the talin2 coding sequence are viable and fertile." Biochemical and biophysical research communications 426(2): 190-195.

 Antibodies are available from Ximbio.com

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