scholarly journals The interaction of IQGAP1 with the exocyst complex is required for tumor cell invasion downstream of Cdc42 and RhoA

2008 ◽  
Vol 181 (6) ◽  
pp. 985-998 ◽  
Author(s):  
Mika Sakurai-Yageta ◽  
Chiara Recchi ◽  
Gaëlle Le Dez ◽  
Jean-Baptiste Sibarita ◽  
Laurent Daviet ◽  
...  
Keyword(s):  
Tumor Cells ◽  
Surface Membrane ◽  
Carcinoma Cells ◽  
Matrix Degradation ◽  
Vesicle Tethering ◽  
Exocyst Complex ◽  
Membrane Protrusions ◽  
Actin Regulatory Proteins ◽  
Membrane Type

Invadopodia are actin-based membrane protrusions formed at contact sites between invasive tumor cells and the extracellular matrix with matrix proteolytic activity. Actin regulatory proteins participate in invadopodia formation, whereas matrix degradation requires metalloproteinases (MMPs) targeted to invadopodia. In this study, we show that the vesicle-tethering exocyst complex is required for matrix proteolysis and invasion of breast carcinoma cells. We demonstrate that the exocyst subunits Sec3 and Sec8 interact with the polarity protein IQGAP1 and that this interaction is triggered by active Cdc42 and RhoA, which are essential for matrix degradation. Interaction between IQGAP1 and the exocyst is necessary for invadopodia activity because enhancement of matrix degradation induced by the expression of IQGAP1 is lost upon deletion of the exocyst-binding site. We further show that the exocyst and IQGAP1 are required for the accumulation of cell surface membrane type 1 MMP at invadopodia. Based on these results, we propose that invadopodia function in tumor cells relies on the coordination of cytoskeletal assembly and exocytosis downstream of Rho guanosine triphosphatases.

scholarly journals Endosomal WASH and exocyst complexes control exocytosis of MT1-MMP at invadopodia

2013 ◽  
Vol 203 (6) ◽  
pp. 1063-1079 ◽  
Author(s):  
Pedro Monteiro ◽  
Carine Rossé ◽  
Antonio Castro-Castro ◽  
Marie Irondelle ◽  
Emilie Lagoutte ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Carcinoma Cells ◽  
General Mechanism ◽  
Pericellular Matrix ◽  
Matrix Degradation ◽  
Late Endosomes ◽  
The Matrix ◽  
Membrane Type ◽  
Syndrome Protein

Remodeling of the extracellular matrix by carcinoma cells during metastatic dissemination requires formation of actin-based protrusions of the plasma membrane called invadopodia, where the trans-membrane type 1 matrix metalloproteinase (MT1-MMP) accumulates. Here, we describe an interaction between the exocyst complex and the endosomal Arp2/3 activator Wiskott-Aldrich syndrome protein and Scar homolog (WASH) on MT1-MMP–containing late endosomes in invasive breast carcinoma cells. We found that WASH and exocyst are required for matrix degradation by an exocytic mechanism that involves tubular connections between MT1-MMP–positive late endosomes and the plasma membrane in contact with the matrix. This ensures focal delivery of MT1-MMP and supports pericellular matrix degradation and tumor cell invasion into different pathologically relevant matrix environments. Our data suggest a general mechanism used by tumor cells to breach the basement membrane and for invasive migration through fibrous collagen-enriched tissues surrounding the tumor.

scholarly journals Increased Aggressiveness of Human Prostate PC-3 Tumor Cells Expressing Cell Surface Localized Membrane Type-1 Matrix Metalloproteinase (MT1-MMP)

2009 ◽  
Vol 30 (3) ◽  
pp. 259-274 ◽  
Author(s):  
X. Wang ◽  
M. J. Wilson ◽  
J. W. Slaton ◽  
A. A. Sinha ◽  
S. L. Ewing ◽  
...  
Keyword(s):  
Cell Surface ◽  
Matrix Metalloproteinase ◽  
Tumor Cells ◽  
Human Prostate ◽  
Membrane Type

scholarly journals Microenvironmental Regulation of Membrane Type 1 Matrix Metalloproteinase Activity in Ovarian Carcinoma Cells via Collagen-induced EGR1 Expression

2006 ◽  
Vol 282 (7) ◽  
pp. 4924-4931 ◽  
Author(s):  
Maria V. Barbolina ◽  
Brian P. Adley ◽  
Edgardo V. Ariztia ◽  
Yueying Liu ◽  
M. Sharon Stack
Keyword(s):  
Matrix Metalloproteinase ◽  
Ovarian Carcinoma ◽  
Three Dimensional ◽  
Carcinoma Cells ◽  
Collagenolytic Activity ◽  
Type I ◽  
Collagen Gels ◽  
Ovarian Carcinoma Cells ◽  
Membrane Type

Late stage ovarian cancer is characterized by disseminated intraperitoneal metastasis as secondary lesions anchor in the type I and III collagen-rich submesothelial matrix. Ovarian carcinoma cells preferentially adhere to interstitial collagen, and collagen-induced integrin clustering up-regulates the expression of the transmembrane collagenase membrane type 1 matrix metalloproteinase (MT1-MMP). Collagenolytic activity is important in intraperitoneal metastasis, potentiating invasion through the mesothelial cell layer and colonization of the submesothelial collagen-rich matrix. The objective of this study was to elucidate a potential mechanistic link between collagen adhesion and MT1-MMP expression. Our results indicate that culturing cells on three-dimensional collagen gels, but not thin layer collagen or synthetic threedimensional hydrogels, results in rapid induction of the transcription factor EGR1. Integrin signaling through a SRC kinase-dependent pathway is necessary for EGR1 induction. Silencing of EGR1 expression using small interfering RNA abrogated collagen-induced MT1-MMP expression and inhibited cellular invasion of three-dimensional collagen gels. These data support a model for intraperitoneal metastasis wherein collagen adhesion and clustering of collagen binding integrins activates integrin-mediated signaling via SRC kinases to induce expression of EGR1, resulting in transcriptional activation of the MT1-MMP promoter and subsequent MT1-MMP-catalyzed collagen invasion. This model highlights the role of unique interactions between ovarian carcinoma cells and interstitial collagens in the ovarian tumor microenvironment in inducing gene expression changes that potentiate intraperitoneal metastatic progression.

scholarly journals A Ca2+-stimulated exosome release pathway in cancer cells is regulated by Munc13-4

2018 ◽  
Vol 217 (8) ◽  
pp. 2877-2890 ◽  
Author(s):  
Scott W. Messenger ◽  
Sang Su Woo ◽  
Zhongze Sun ◽  
Thomas F.J. Martin
Keyword(s):  
Extracellular Matrix ◽  
Cancer Cells ◽  
Multivesicular Bodies ◽  
Matrix Degradation ◽  
Cellular Mechanisms ◽  
Trafficking Pathway ◽  
Acute Elevation ◽  
Membrane Type ◽  
Dependent Pathway

Cancer cells secrete copious amounts of exosomes, and elevated intracellular Ca2+ is critical for tumor progression and metastasis, but the underlying cellular mechanisms are unknown. Munc13-4 is a Ca2+-dependent SNAP receptor– and Rab-binding protein required for Ca2+-dependent membrane fusion. Here we show that acute elevation of Ca2+ in cancer cells stimulated a fivefold increase in CD63+, CD9+, and ALIX+ exosome release that was eliminated by Munc13-4 knockdown and not restored by Ca2+ binding–deficient Munc13-4 mutants. Direct imaging of CD63-pHluorin exosome release confirmed its Munc13-4 dependence. Depletion of Munc13-4 in highly aggressive breast carcinoma MDA-MB-231 cells reduced the size of CD63+ multivesicular bodies (MVBs), indicating a role for Munc13-4 in MVB maturation. Munc13-4 used a Rab11-dependent trafficking pathway to generate MVBs competent for exosome release. Membrane type 1 matrix metalloproteinase trafficking to MVBs by a Rab11-dependent pathway was also Munc13-4 dependent, and Munc13-4 depletion reduced extracellular matrix degradation. These studies identify a novel Ca2+- and Munc13-4-dependent pathway that underlies increased exosome release by cancer cells.

Functional activation of integrin ?v?3 in tumor cells expressing membrane-type 1 matrix metalloproteinase

2000 ◽  
Vol 86 (1) ◽  
pp. 15-23 ◽  
Author(s):  
Elena I. Deryugina ◽  
Mario A. Bourdon ◽  
Karli Jungwirth ◽  
Jeffrey W. Smith ◽  
Alex Y. Strongin
Keyword(s):  
Matrix Metalloproteinase ◽  
Tumor Cells ◽  
Membrane Type

scholarly journals CAIX Regulates Invadopodia Formation through Both a pH-Dependent Mechanism and Interplay with Actin Regulatory Proteins

2019 ◽  
Vol 20 (11) ◽  
pp. 2745 ◽  
Author(s):  
Michaela Debreova ◽  
Lucia Csaderova ◽  
Monika Burikova ◽  
Lubomira Lukacikova ◽  
Ivana Kajanova ◽  
...  
Keyword(s):  
Tumor Cells ◽  
Actin Polymerization ◽  
Ph Regulation ◽  
Matrix Degradation ◽  
Lung Colonization ◽  
Actin Regulatory Proteins ◽  
And Migration ◽  
The Impact ◽  
Invadopodia Formation

Tumor metastasis is tightly linked with invasive membrane protrusions, invadopodia, formed by actively invading tumor cells. Hypoxia and pH modulation play a role in the invadopodia formation and in their matrix degradation ability. Tumor-associated carbonic anhydrase IX (CAIX), induced by hypoxia, is essential for pH regulation and migration, predisposing it as an active component of invadopodia. To investigate this assumption, we employed silencing and inhibition of CA9, invadopodia isolation and matrix degradation assay. Quail chorioallantoic membranes with implanted tumor cells, and lung colonization assay in murine model were used to assess efficiency of in vivo invasion and the impact of CAIX targeting antibodies. We showed that CAIX co-distributes to invadopodia with cortactin, MMP14, NBCe1, and phospho-PKA. Suppression or enzymatic inhibition of CAIX leads to impaired invadopodia formation and matrix degradation. Loss of CAIX attenuated phosphorylation of Y421-cortactin and influenced molecular machinery coordinating actin polymerization essential for invadopodia growth. Treatment of tumor cells by CAIX-specific antibodies against carbonic or proteoglycan domains results in reduced invasion and extravasation in vivo. For the first time, we demonstrated in vivo localization of CAIX within invadopodia. Our findings confirm the key role of CAIX in the metastatic process and gives rationale for its targeting during anti-metastatic therapy.

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