MT1-MMP prevents growth inhibition by three dimensional fibronectin matrix

Takino, Takahisa; Guo, Luyang; Domoto, Takahiro; Sato, Hiroshi

doi:10.1016/j.bbrc.2013.05.134

Cited by 6 publications

(6 citation statements)

References 29 publications

(18 reference statements)

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“…The interaction between β1 integrin and MT1-MMP blocks MT1-MMP internalization and causes increased MMP-2 activation. It is now widely accepted that MT1-MMP is regulated by and/or associated with integrin/FAK/Src/P13C as a pathway to promote pericellular proteolysis and invasion in 3-dimensional cultures [ 54 ], in part due to focal adhesion turnover [ 55 , 56 ]. FAK-mediated src phosphorylation of endophilin A2 inhibits endocytosis of MT1-MMP and promotes ECM degradation [ 57 ].…”

Section: Discussionmentioning

confidence: 99%

High threshold of β1 integrin inhibition required to block collagen I-induced membrane type-1 matrix metalloproteinase (MT1-MMP) activation of matrix metalloproteinase 2 (MMP-2)

et al. 2014

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BackgroundMatrix metalloproteinase-2 (MMP-2) is an endopeptidase that facilitates extracellular matrix remodeling and molecular regulation, and is implicated in tumor metastasis. Type I collagen (Col I) regulates the activation of MMP-2 through both transcriptional and post-transcriptional means; however gaps remain in our understanding of the involvement of collagen-binding β1 integrins in collagen-stimulated MMP-2 activation.MethodsThree β1 integrin siRNAs were used to elucidate the involvement of β1 integrins in the Col I-induced MMP-2 activation mechanism. β1 integrin knockdown was analyzed by quantitative RT-PCR, Western Blot and FACS analysis. Adhesion assay and collagen gel contraction were used to test the biological effects of β1 integrin abrogation. MMP-2 activation levels were monitored by gelatin zymography.ResultsAll three β1 integrin siRNAs were efficient at β1 integrin knockdown and FACS analysis revealed commensurate reductions of integrins α2 and α3, which are heterodimeric partners of β1, but not αV, which is not. All three β1 integrin siRNAs inhibited adhesion and collagen gel contraction, however only the siRNA showing the greatest magnitude of β1 knockdown inhibited Col I-induced MMP-2 activation and reduced the accompanying upregulation of MT1-MMP, suggesting a dose response threshold effect. Re-transfection with codon-swapped β1 integrin overcame the reduction in MMP-2 activation induced by Col-1, confirming the β1 integrin target specificity. MMP-2 activation induced by TPA or Concanavalin A (Con A) was not inhibited by β1 integrin siRNA knockdown.ConclusionTogether, the data reveals that strong abrogation of β1 integrin is required to block MMP-2 activation induced by Col I, which may have implications for the therapeutic targeting of β1 integrin.

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Section: Discussionmentioning

confidence: 99%

High threshold of β1 integrin inhibition required to block collagen I-induced membrane type-1 matrix metalloproteinase (MT1-MMP) activation of matrix metalloproteinase 2 (MMP-2)

et al. 2014

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“…For example, when embedded in 3D collagen and accompanied with a non-phosphorylable mutation of MT1-MMP, HT-1080 showed a markedly reduced proliferation rate and G 0 /G 1 phase cell cycle arrest [64]. However, after MT1-MMP was activated by integrin β 1 knockout through the NF-κB pathway, HT-1080 could enter the S phase cell cycle and restore normal growth in a 3D FN matrix [65]. These results suggest that MT1-MMP can be mediated through integrin β 1 to regulate the growth of 3D cultured sarcoma cells [65].…”

Section: Effect On Cell Invasionmentioning

confidence: 99%

Three-dimensional (3D) culture in sarcoma research and the clinical significance

et al. 2017

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Sarcomas are rare malignant tumors that arise from transformed cells of mesenchymal origin. Despite the progress in diagnosis and treatment, sarcomas have a high mortality rate due to local recurrence, metastasis, and the development of drug resistance to chemotherapy. New models for sarcoma research are required to further understand the disease and to develop new therapies. In vitro sarcoma modeling is challenging because of significant genetic heterogeneities, diverse pathological, and overlapping clinical characteristics. Studies on the mechanisms of recurrence, metastasis, and drug resistance in sarcoma have resulted in the generation of novel three-dimensional (3D) culture models for sarcoma research. 3D culture models aim to recapitulate the tumor microenvironment that plays a critical role in the pathogenesis of sarcoma using biomaterial scaffolds of natural biological materials and artificial polymers. An ideal 3D culture model can properly mimic not only the microenvironment, oncogenesis, and maintenance of sarcoma cell growth, but also imitate the interactions between cells and to the extracellular matrix. More recently, 3D cell culture has been used to research the biological behavior and mechanism of chemotherapy and radiotherapy resistance in different sarcoma models. Ultimately, findings using 3D models that more accurately reflect human sarcoma biology are likely to translate into improved clinical outcomes. In this review, we discuss the most recent advances of 3D culture technologies in sarcoma research and emerging clinical applications.

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“…In cancer, various MMPs are responsible for the degradation of nearly all extracellular matrix and basement membrane components, allowing cells to delaminate from and invade into intact tissue (d’Ortho et al, 1997; Roy et al, 2009; Tzanakakis et al, 2018). They can also cleave cell adhesion molecules critical for EMT and cell migration (Covington et al, 2006; Symowicz et al, 2007; Takino et al, 2013; Porlan et al, 2014). Among 25 members of MMPs, MM14 (or MT1-MMP) is identified as the most effective in matrix proteolysis and subsequent cell migration (Itoh and Seiki, 2006).…”

Section: Introductionmentioning

confidence: 99%

MMP14 Regulates Cranial Neural Crest Epithelial‐to‐Mesenchymal Transition and Migration

Garmon

Wittling

Nie

2018

Developmental Dynamics

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MT1-MMP prevents growth inhibition by three dimensional fibronectin matrix

Cited by 6 publications

References 29 publications

High threshold of β1 integrin inhibition required to block collagen I-induced membrane type-1 matrix metalloproteinase (MT1-MMP) activation of matrix metalloproteinase 2 (MMP-2)

High threshold of β1 integrin inhibition required to block collagen I-induced membrane type-1 matrix metalloproteinase (MT1-MMP) activation of matrix metalloproteinase 2 (MMP-2)

Three-dimensional (3D) culture in sarcoma research and the clinical significance

MMP14 Regulates Cranial Neural Crest Epithelial‐to‐Mesenchymal Transition and Migration

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