J Victor Small — Page 2

PubMed2002

PIP(2)-PDZ domain binding controls the association of syntenin with the plasma membrane.

PDZ proteins organize multiprotein signaling complexes. According to current views, PDZ domains engage in protein-protein interactions. Here we show that the PDZ domains of several proteins bind phosphatidylinositol 4,5-bisphosphate (PIP(2)). High-affinity binding of syntenin to PIP(2)-containing lipid layers requires both PDZ domains of this protein. Competition and mutagenesis experiments reveal that the protein and the PIP(2) binding sites in the PDZ domains overlap. Overlay assays indicate that the two PDZ domains of syntenin cooperate in binding to cognate peptides and PIP(2). Experiments on living cells demonstrate PIP(2)-dependent and peptide-dependent modes of plasma membrane association of the PDZ domains of syntenin. These observations suggest that local changes in phosphoinositide concentration control the association of PDZ proteins with their target receptors at the plasma membrane.

Animals↗

PubMed2002

Regulation of substrate adhesion dynamics during cell motility.

The movement of a metazoan cell entails the regulated creation and turnover of adhesions with the surface on which it moves. Adhesion sites form as a result of signaling between the extracellular matrix on the outside and the actin cytoskeleton on the inside, and they are associated with specific assembles of actin filaments. Two broad categories of adhesion sites can be distinguished: (1) "focal complexes" associated with lamellipodia and filopodia that support protrusion and traction at the cell front; and (2) "focal adhesions" at the termini of stress fibre bundles that serve in longer term anchorage. Focal complexes are signaled via Rac1 or Cdc42 and can either turnover on a minute scale or differentiate, via intervention of the RhoA pathway, into longer-lived focal adhesions. All classes of adhesion sites depend on the stress in the actin cytoskeleton for their formation and maintenance. Different cell types use different adhesion strategies to move, in terms of the relative engagement of filopodia and lamellipodia in focal complex formation and protrusion and the extent of focal adhesion formation. These differences can be attributed to variations in the relative activities of Rho family members. However, the Rho GTPases alone are unable to signal asymmetry in the actin cytoskeleton, necessary for polarisation and movement. Polarisation requires the collaboration of the microtubule cytoskeleton. Changes in the polymerisation state of microtubules influences the activities of both Rac1 and RhoA and microtubules interact directly with adhesion foci and promote their turnover. Possible mechanisms of cross-talk between the microtubule and actin cytoskeletons in determining polarity are discussed.

Actins↗

PubMed2002

How do microtubules guide migrating cells?

Microtubules have long been implicated in the polarization of migrating cells, but how they carry out this role is unclear. Here, we propose that microtubules determine cell polarity by modulating the pattern of adhesions that a cell develops with the underlying matrix, through focal inhibitions of contractility.

Actins↗