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 bin ds to the underlying collagen. It is envisaged that cells proceed by a process of engagement and disengagement of av integrins to the extrac ellular matrix, somewhat analogous to the motion of a monkey climbing a tree. Secretion of isoforms of the adhesion modulator, thrombospondi n, regulates disengagement of the integrin from its ligand in migratin g cells. The integrin disengagement signal is mediated by thrombospond in cross-linking the alphav integrin to an integrin accessory molecule and thus activating protein kinases. The cross-linked receptor comple x undergoes recycling back along actin stress fibres, guided by the in tegrin beta-subunit. After endocytosis and protein sorting the alphav integrin is transported back to the leading edge off migrating cells i n vesicles guided by the tubulin-binding capabilities of an integrin a ccessory molecule. Direct attachment to collagen required for processe s, such as matrix contraction, is mediated by VLA integrins which disp lace av integrins from points of attachment during integrin recycling, possibly through an alphavbeta1 intermediary receptor.