Basolateral localization of MMP14 drives apicobasal polarity change during EMT independently of its catalytic activity

Abstract

The transmembrane Matrix Metalloproteinase MMP14/MT1-MMP is known to promote cell migration by cleavage of the extracellular matrix. To initiate migration, epithelial cells need to gain mesenchymal attributes. They reduce cell-cell junctions and apicobasal polarity and gain migratory capabilities. This process is named epithelial-mesenchymal transition (EMT).MMP14's implication in EMT is still ill-defined. We used chick neural crest (NC) cells as a model to explore the function of MMP14 in physiological EMT. Our results show that MMP14 is expressed by chick NC cells. However, it is its subcellular localization, rather than its expression, that correlates with EMT. MMP14 is first apical and switches to basolateral domains during EMT. Loss of function and rescue experiments show that MMP14 is involved in EMT independently of its catalytic activity. It lies downstream of pro-EMT genes and upstream of cell polarity. We found that basolateral localization of MMP14 is required and sufficient to induce polarity change in NC cells and neuroepithelial cells, respectively. These effects on polarity occur without impact on cell-cell adhesion or the extracellular matrix.Overall, our data points to a new function of MMP14 in EMT that will need to be further explored in other systems such as cancer cells.

Conserved role of matrix metalloproteases 2 and 9 in promoting the migration of neural crest cells in avian and mammalian embryos

“…These phenotypes, which are associated with defects in the ontogeny of cranial NCC derivatives, suggest that MMP14 is able to compensate for the loss of MMP16 in the mutant such that only the double KO yielded craniofacial defects. Notably, ours and others recent studies reported that MMP14 and MMP16 participate in executing NCC migration in Xenopus laevis and chick, respectively . Hence, MMP14 and MMP16 seem to also be necessary for multiple stages of NCC development, similar to MMP2 and MMP9.…”

“…Notably, ours and others recent studies reported that MMP14 and MMP16 participate in executing NCC migration in Xenopus laevis and chick, respectively. 44,82,83 Hence, MMP14 and MMP16 seem to also be necessary for multiple stages of NCC development, similar to MMP2 and MMP9. Future studies will be required to elucidate how these subgroups of MMPs cooperate in the regulation of NCC migration in different types of embryos.…”

Prickle1 is required for EMT and migration of zebrafish cranial neural crest

“…In Xenopus embryos, the Smad-interacting protein-1 (Sip-1)-known to repress E-Cad expression in cancer cells-is required for NCCs to complete EMT, disperse, and migrate out from dorsal positions of the neural tube (Rogers et al, 2013). The metalloproteinase MMP14, through control of both E-Cad and N-Cad, also regulates both EMT and migration (Garmon et al, 2018), at least in part through a change in apicobasal polarity (Andrieu et al, 2018). Transcription factors such as Ets (Theveneau et al, 2007) and the Wnt signaling effector Axud1 (Simoes-Costa et al, 2015) are also required for the successful separation of NCCs from the neuroepithelium, with the latter additionally playing an earlier role in NCC specification.…”

Implicación de la MMP-14 en la Homeostasis y Regeneración muscular tras daño y enfermedad

“…De hecho, nuestro estudio muestra una distribución polarizada de la MMP-14 en los dobletes celulares de ratones wild type, mostrando que la deficiencia de esta proteasa puede interferir en la simetría celular. En concordancia con este dato, durante la transición epitelio-mesénquima, la MMP-14 se asociada a la integrina-β1 localizada en el lado apical de la célula, trasladándose al lado basal durante la migración celular al interaccionar con la integrina-β3, proceso mediado por el dominio extracelular de la MMP-14, independientemente de su actividad catalítica290 .El hecho de que las MMPs, y en concreto la MMP-14, participen en la polaridad celular podría explicar además la distribución asimétrica de distintos componentes de la MEC durante las divisiones de las células satélite. Por ejemplo, la presencia de laminina-a1 en la lámina basal del…”

“…También es necesario considerar la complejidad de la MMP-14, que además de procesar proteínas estructurales de la MEC puede degradar moléculas de señalización pro-fibróticas como TNF-b, moléculas de la superficie celular como integrinas y quimoquinas o factores de crecimiento como FGF315,329 , que pueden afectar directamente a las células satélite o indirectamente, afectando a otras células que conforman su nicho y que participan en la regeneración muscular22 . Además, la MMP-14 no sólo media procesos celulares a través de su función proteolítica, pudiendo actuar también sobre distintas rutas de señalización a través de su cola citoplasmática194 o su dominio extracelular290 .…”