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J Cell Sci. 2013 Jul 1;126(Pt 13):2820-33. doi: 10.1242/jcs.122358. Epub 2013 Apr 19.

A specific subset of RabGTPases controls cell surface exposure of MT1-MMP, extracellular matrix degradation and three-dimensional invasion of macrophages.

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1
Institut für medizinische Mikrobiologie, Virologie und Hygiene, Universitätsklinikum Eppendorf, Martinistr. 52, 20246 Hamburg, Germany.

Abstract

The matrix metalloproteinase MT1-MMP has a major impact on invasive cell migration in both physiological and pathological settings such as immune cell extravasation or metastasis of cancer cells. Surface-associated MT1-MMP is able to cleave components of the extracellular matrix, which is a prerequisite for proteolytic invasive migration. However, current knowledge on the molecular mechanisms that regulate MT1-MMP trafficking to and from the cell surface is limited. We have identified three members of the RabGTPase family, Rab5a, Rab8a and Rab14, as crucial regulators of MT1-MMP trafficking and function in primary human macrophages. Both overexpressed and endogenous forms show prominent colocalisation with MT1-MMP-positive vesicles, whereas expression of mutant constructs, as well as siRNA-induced knockdown, reveal that these RabGTPases are crucial in the regulation of MT1-MMP surface exposure, contact of MT1-MMP-positive vesicles with podosomes, extracellular matrix degradation in two and three dimensions, as well as three-dimensional proteolytic invasion of macrophages. Collectively, our results identify Rab5a, Rab8a and Rab14 as major regulators of MT1-MMP trafficking and invasive migration of primary human macrophages, which could be promising potential targets for manipulation of immune cell invasion.

KEYWORDS:

Cell invasion; Extracellular matrix; MT1-MMP; Podosomes; RabGTPases

PMID:
23606746
DOI:
10.1242/jcs.122358
[Indexed for MEDLINE]
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