Control of MT1-MMP transport by atypical PKC during breast-cancer progression

Abstract

Dissemination of carcinoma cells requires the pericellular degradation of the extracellular matrix, which is mediated by membrane type 1-matrix metalloproteinase (MT1-MMP). In this article, we report a co-up-regulation and colocalization of MT1-MMP and atypical protein kinase C iota (aPKCι) in hormone receptor-negative breast tumors in association with a higher risk of metastasis. Silencing of aPKC in invasive breast-tumor cell lines impaired the delivery of MT1-MMP from late endocytic storage compartments to the surface and inhibited matrix degradation and invasion. We provide evidence that aPKCι, in association with MT1-MMP-containing endosomes, phosphorylates cortactin, which is present in F-actin-rich puncta on MT1-MMP-positive endosomes and regulates cortactin association with the membrane scission protein dynamin-2. Thus, cell line-based observations and clinical data reveal the concerted activity of aPKC, cortactin, and dynamin-2, which control the trafficking of MT1-MMP from late endosome to the plasma membrane and play an important role in the invasive potential of breast-cancer cells.membrane traffic | actin cytoskeleton | multi-vesicular body | MMP14

Endophilin A2 Promotes TNBC Cell Invasion and Tumor Metastasis

“…We hypothesize that lack of an endosomal pool of MT1-MMP may limit subsequent delivery to invadopodia precursors in Endo II KD TNBC cells. It is worth noting that the Endo II binding partner Dynamin has recently been implicated in the formation and fission of tubulovesicular carriers from this intracellular pool of MT1-MMP (44). Like our findings here for Endo II, Dynamin was also identified as a positive regulator of invadopodia formation and cell invasion in MDA-MB-231 cells (45).…”

Heterotrimeric G Proteins Directly Regulate MMP14/Membrane Type-1 Matrix Metalloprotease

“…Perhaps GPCRs and heterotrimeric G proteins release other such entities. In addition, MMP14 and RTKs have been implicated in other cellular responses and disease settings (4,(43)(44)(45). We speculate that the activation of MMP14 by heterotrimeric G proteins may contribute to such responses and diseases and that therapeutic approaches designed to block heterotrimeric G protein-mediated activation of MMP14 may be useful in such settings.…”

Moesin regulates the motility of oral cancer cells via MT1-MMP and E-cadherin/p120-catenin adhesion complex

“…MT1-MMP has been referred to as a multi-functional protein involved in ECM degradation, angiogenesis and MMP-2 activation [28] and promotes tumor invasion [29]. Recently, it has been reported that MT1-MMP accumulates at the leading edge of invasion and invadopodia which are actin-rich membrane protrusions specialized for ECM degradation during cell invasion [30,31], and the recruitment of the cytoskeletal protein cortactin and MT1-MMP is pivotal for the maturation of functional invadopodia [32].…”