INVOLVEMENT OF MICROTUBULES IN THE CONTROL OF ADHESION-DEPENDENT SIGNAL-TRANSDUCTION

Background: The adhesion of cells to the extracellular matrix (ECM) ge nerates transmembrane signals that affect cell proliferation, differen tiation and survival. These signals are triggered by interactions betw een integrin and the ECM and involve tyrosine phosphorylation of speci fic proteins, including focal adhesion kinase (FAK) and paxillin, and the assembly of focal adhesions and actin bundles. In matrix-adherent, serum-starved Swiss 3T3 cells, the system of focal adhesions and acti n bundles is poorly developed, and the level of tyrosine phosphorylati on of FAK and paxillin is low. A number of growth factors rapidly stim ulate tyrosine phosphorylation of these proteins and the assembly of f ocal adhesions and actin bundles. Growth factors and adhesion to the E CM are both necessary for the subsequent transition of cells to the S- phase of the cell cycle. Results: In serum-starved Swiss 3T3 cells, th e disruption of microtubules by nocodazole or vinblastine, without the addition of external growth factors, induces the rapid assembly of fo cal adhesions and microfilament bundles, tyrosine phosphorylation of F AK and paxillin, and subsequent enhancement of DNA synthesis. All thes e effects require cell adhesion to the ECM and do not occur when cells are plated on substrates coated with poly-L-lysine or concanavalin A. Inhibitors of tyrosine phosphorylation and cell contractility also el iminate the effects of microtubule disruption on adhesion-dependent si gnal transduction. Conclusions: In ECM-attached cells, microtubule dis ruption activates the integrin-dependent signaling cascade, which lead s to the assembly of matrix adhesions and the induction of DNA synthes is. The increase in cell contractility is an indispensable intermediat e step in this signaling process. (C) Current Biology Ltd ISSN 0960-98 22