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.
Keywords:
MMP14; actin cytoskeleton; membrane traffic; multi-vesicular body.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenocarcinoma / genetics
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Adenocarcinoma / metabolism
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Adenocarcinoma / pathology
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Adult
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Aged
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Biological Transport, Active
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Breast Neoplasms / genetics
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Breast Neoplasms / metabolism*
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Breast Neoplasms / pathology
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Carcinoma, Ductal, Breast / genetics
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Carcinoma, Ductal, Breast / metabolism
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Carcinoma, Ductal, Breast / pathology
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Cell Line, Tumor
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Cortactin / metabolism
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Cytoplasmic Granules / metabolism
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Disease Progression
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Dynamin II / metabolism
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Endosomes / metabolism
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Extracellular Matrix / metabolism
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Female
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Humans
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Isoenzymes / antagonists & inhibitors
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Isoenzymes / genetics
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Isoenzymes / metabolism*
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Matrix Metalloproteinase 14 / genetics
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Matrix Metalloproteinase 14 / metabolism*
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Middle Aged
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Neoplasm Invasiveness
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Phosphorylation
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Protein Kinase C / antagonists & inhibitors
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Protein Kinase C / genetics
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Protein Kinase C / metabolism*
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RNA Interference
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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RNA, Neoplasm / genetics
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RNA, Neoplasm / metabolism
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RNA, Small Interfering / genetics
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Up-Regulation
Substances
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CTTN protein, human
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Cortactin
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Isoenzymes
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RNA, Messenger
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RNA, Neoplasm
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RNA, Small Interfering
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protein kinase C zeta
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Protein Kinase C
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protein kinase C lambda
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MMP14 protein, human
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Matrix Metalloproteinase 14
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Dynamin II