A REEXAMINATION OF THE MOLECULAR-BASIS OF CELL-MOVEMENT

A model for cell movement is presented. it is suggested that cells do not migrate on collagen using their VLA (very late antigen) integrins that bind this extracellular matrix protein. Rather, the cells utilize alphav integrins to bind endogenously produced fibronectin, which binds to the underlying collagen. It is envisaged that cells proceed by a process of engagement and disengagement of av integrins to the extracellular matrix, somewhat analogous to the motion of a monkey climbing a tree. Secretion of isoforms of the adhesion modulator, thrombospondin, regulates disengagement of the integrin from its ligand in migrating cells. The integrin disengagement signal is mediated by thrombospondin cross-linking the alphav integrin to an integrin accessory molecule and thus activating protein kinases. The cross-linked receptor complex undergoes recycling back along actin stress fibres, guided by the integrin beta-subunit. After endocytosis and protein sorting the alphav integrin is transported back to the leading edge off migrating cells in vesicles guided by the tubulin-binding capabilities of an integrin accessory molecule. Direct attachment to collagen required for processes, such as matrix contraction, is mediated by VLA integrins which displace av integrins from points of attachment during integrin recycling, possibly through an alphavbeta1 intermediary receptor.