The Kinesin KIF1C and Microtubule Plus Ends Regulate Podosome Dynamics in Macrophages

Abstract

Microtubules are important for the turnover of podosomes, dynamic, actin-rich adhesions implicated in migration and invasion of monocytic cells. The molecular basis for this functional dependency, however, remained unclear. Here, we show that contact by microtubule plus ends critically influences the cellular fate of podosomes in primary human macrophages. In particular, we identify the kinesin KIF1C, a member of the Kinesin-3 family, as a plus-end-enriched motor that targets regions of podosome turnover. Expression of mutation constructs or small interfering RNA-/short hairpin RNA-based depletion of KIF1C resulted in decreased podosome dynamics and ultimately in podosome deficiency. Importantly, protein interaction studies showed that KIF1C binds to nonmuscle myosin IIA via its PTPD-binding domain, thus providing an interface between the actin and tubulin cytoskeletons, which may facilitate the subcellular targeting of podosomes by microtubules. This is the first report to implicate a kinesin in podosome regulation and also the first to describe a function for KIF1C in human cells.

p190B RhoGAP regulates endothelial-cell-associated proteolysis through MT1-MMP and MMP2

“…Because it has been suggested that the degradation activity is directly correlated to the half-life of the structures (Linder, 2007), the observed increase of these two parameters might in fact reflect a reduction in podosome turnover in p190A-KD cells. The microtubule cytoskeleton was shown to be involved in podosome dynamics in macrophages (Kopp et al, 2006); however, we were not able to detect any alteration in the pattern of α-tubulin in these modified cells. Thus, our data suggest that, even if p190A and p190B proteins share a high degree of homology and are involved in similar signalling cascades, they might control actin-cytoskeleton-based processes through distinct mechanisms.…”

The interplay between the proteolytic, invasive, and adhesive domains of invadopodia and their roles in cancer invasion

“…Nevertheless, intact microtubules are required for the function of other invadosomes, such as podosomes of monocytes, macrophages, and osteoclasts 1,112,113 . In breast cancer cells, intact microtubules are not necessary for invadopodia formation, 114,115 but their destruction affects invadopodia elongation and maturation.…”

Invadosomes at a glance

“…Finally, microtubules and microtubulebased motor proteins such as the kinesin KIF1C also play a role in the fission (the formation of new podosomes by splitting off from larger precursors) and dissolution processes of podosomes in human macrophages (Kopp et al, 2006).…”

“…Accordingly, myosin II has been localized to podosomes in osteoclasts (Krits et al, 2002) and dendritic cells (van Helden et al, 2008), in which it surrounds the core structure. Conflicting data exist about the exact role of myosin (Burgstaller and Gimona, 2005;Clark et al, 2006;Kopp et al, 2006;Collin et al, 2008), but a possibly unifying hypothesis proposes that basal myosin-II activity is required for the formation and maintenance of podosomes, whereas sudden increases in myosin-II activity trigger podosome dissolution (van Helden et al, 2008). Myosin-generated contractility can, depending on substrate stiffness, also be translated into traction forces beneath podosomes, which would enable them to function as mechanosensors (Collin et al, 2008).…”