Modulation of substrate adhesion dynamics via microtubule targeting requires kinesin-1

Abstract

Recent studies have shown that the targeting of substrate adhesions by microtubules promotes adhesion site disassembly (Kaverina, I., O. Krylyshkina, and J.V. Small. 1999. J. Cell Biol. 146:1033–1043). It was accordingly suggested that microtubules serve to convey a signal to adhesion sites to modulate their turnover. Because microtubule motors would be the most likely candidates for effecting signal transmission, we have investigated the consequence of blocking microtubule motor activity on adhesion site dynamics. Using a function-blocking antibody as well as dynamitin overexpression, we found that a block in dynein–cargo interaction induced no change in adhesion site dynamics in Xenopus fibroblasts. In comparison, a block of kinesin-1 activity, either via microinjection of the SUK-4 antibody or of a kinesin-1 heavy chain construct mutated in the motor domain, induced a dramatic increase in the size and reduction in number of substrate adhesions, mimicking the effect observed after microtubule disruption by nocodazole. Blockage of kinesin activity had no influence on either the ability of microtubules to target substrate adhesions or on microtubule polymerisation dynamics. We conclude that conventional kinesin is not required for the guidance of microtubules into substrate adhesions, but is required for the focal delivery of a component(s) that retards their growth or promotes their disassembly.

Overexpression of autocrine motility factor in metastatic tumor cells: possible association with augmented expression of KIF3A and GDI-β

“…56 Recently, kinesin has shown to be required for the focal delivery of possible components to retard substrate adhesions' growth or promote their disassembly. 57 In the present study, amf/phi-transfected cells showing high motility exhibited not only augmented expression of KIF3A but also a tendency of distribution shift to the cell periphery. KIF3A may play an important role in the focal delivery of a component(s) that modulates the dynamics of adhesive structures at the focal contact, and then stimulate cell motility.…”

“…30 These molecules corresponded well with components that are possible molecules specifically accumulated at microtubule tips as cofactors, together with cargo delivered by kinesin, in signal transduction events. 57 Small GTPase rho and the downstream effecter molecules may be possible components to which KIF3A may be related, delivering to the cell periphery in association with microtubules in AMF/PHI-stimulated cells.…”

Scaffold mediated regulation of MAPK signaling and cytoskeletal dynamics: A perspective

“…Time lapse imaging studies indicated that growing microtubules target focal adhesions for subsequent disassembly [133,136]. A single focal adhesion may be targeted multiple times and a single microtubule tip may target multiple focal adhesions suggesting dynamic interaction of microtubule and actin filament systems and their associated molecular motors [136,137]. Consistent with this view, inhibiting the kinesin motors (predominantly plus-end directed motors of the microtubule system) can interfere with focal adhesion disassembly without affecting microtubule dynamics or targeting to focal adhesions [137,138].…”

“…A single focal adhesion may be targeted multiple times and a single microtubule tip may target multiple focal adhesions suggesting dynamic interaction of microtubule and actin filament systems and their associated molecular motors [136,137]. Consistent with this view, inhibiting the kinesin motors (predominantly plus-end directed motors of the microtubule system) can interfere with focal adhesion disassembly without affecting microtubule dynamics or targeting to focal adhesions [137,138]. Thus, microtubules may direct kinesin motors bound to disassembly factors to focal sites to promote adhesion turn over.…”

“…Thus, microtubules may direct kinesin motors bound to disassembly factors to focal sites to promote adhesion turn over. The molecular nature of factors that are delivered to focal adhesions by microtubules have remained elusive [134,137,139] but might include the class of calcium activated proteases, calpains [140,141] (see below). Interestingly, Ezratty et.…”