Bass et al.
During cell migration, the actin cytoskeleton regulator, RhoA, must be alternately inhibited (to allow the leading membrane edge to protrude) and reactivated (to pull up the trailing end of the cell from behind). Inhibition occurs when a receptor called α5β1 integrin, which binds to the extracellular matrix protein, fibronectin, triggers phosphorylation of a RhoA inhibitor called p190RhoGAP-A (p190-A). Another fibronectin receptor, syndecan-4, colocalizes with integrin during RhoA inhibition, but whether this second receptor contributes to inhibition was unknown.
By treating cells with fragments of fibronectin that bound to syndecan-4 but not integrin, the authors showed that syndecan-4 triggered transient relocation of p190-A to the membrane, which correlated with reduced RhoA activity. Syndecan-4 is known to activate PKCα, and exogenous activation of PKCα is known to trigger phosphorylation and membrane recruitment of p190-A. Bass et al. connected the dots by showing that loss of syndecan-4 function reduced relocation of p190-A to the membrane. Although integrin phosphorylates p190-A at a tyrosine, syndecan-4 phosphorylated a serine. Neither integrin nor syndecan alone induced the normal Rho-related pattern of cell spreading, suggesting that a combination of these two receptors is needed for full inhibition of RhoA.
p190-A is the convergence point for signaling from these two independent adhesion receptors, the authors conclude. Although the two receptors colocalize during leading edge protrusion, syndecan-4, a lengthy protein, can stretch itself up to 500 nm from the cell. Syndecan-4 might therefore act as an exploratory receptor, whereas the shorter integrin may anchor the leading edge. In this model, p190-A serves to integrate information from both near and far.