MT1-MMP Down-regulates the Glucose 6-Phosphate Transporter Expression in Marrow Stromal Cells

Abstract

Recent advances in the understanding of stem cell mobilization, cell-matrix interaction, and biodistribution have enabled the development of new therapeutic strategies (1, 2). Although locally transplanted bone marrow-derived stromal cells (BMSC) 2 have already been used clinically (3-5), less invasive routes of BMSC transplantation have become the focus of recent attention (6 -8). In fact, several clinical applications now use intravenous administration of genetically engineered BMSC either as an ideal vehicle for gene transfer or as a platform for the systemic delivery of therapeutic recombinant proteins in vivo (6,9,10). This implies that these circulating, systemically infused cells must respond to serum-derived cues that direct their ultimate biodistribution. The molecular players regulating cellular mobilization, chemotaxis, and cell survival of BMSC have received little attention.Among the mediators known to exert potent cellular chemotactic effects, sphingosine 1-phosphate (S1P) is one of the most important bioactive lysophospholipids secreted in blood plasma either upon platelet activation (11) or from brain tumor-derived glioma cells (12). In fact, we have demonstrated that BMSC chemotaxis was very strong in response to S1P (13) and required reorganization of the actin cytoskeleton and remodeling of the extracellular matrix (ECM) through a complex, cooperative signal transduction network involving cell surface matrix metalloproteinase (MMP) activity (14). Currently, the molecular characterization and the nature of that MMP, regulating both BMSC chemotaxis and interaction with the ECM protein microenvironment, remain poorly understood. Recently, we highlighted functional cross-talk between the membrane type-1 MMP (MT1-MMP) and the S1P receptor EDG-1-mediated signaling in BMSC chemotaxis (13). Interestingly, aside from its classical role in ECM proteolysis, MT1-MMP is also involved in transducing crucial intracellular signaling that may control several processes related to BMSC mobilization and cell survival (13)(14)(15)(16).Given that impaired chemotaxis was recently observed in bone marrow cells isolated from a microsomal glucose 6-phos-* This work was supported by a grant of the Natural Sciences and EngineeringResearch Council of Canada (NSERC) (to B. A.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. 2 The abbreviations used are: BMSC, bone marrow-derived stromal cell(s); ConA, concanavalin A; ECM, extracellular matrix; G6P, glucose 6-phosphate; G6Pase, glucose-6-phosphatase; G6PT, G6P transporter; MMP, matrix metalloproteinase; MT1-MMP, membrane type-1 MMP; PI, propidium iodine; siRNA, small interfering RNA; S1P, sphingosine 1-phosphate; PBS, phosphate-buffered saline; Wt, wild type; GFP, green fluorescent protein.

Epigallocatechin Gallate Targeting of Membrane Type 1 Matrix Metalloproteinase-mediated Src and Janus Kinase/Signal Transducers and Activators of Transcription 3 Signaling Inhibits Transcription of Colony-stimulating Factors 2 and 3 in Mesenchymal Stromal Cells

“…Src-mediated phosphorylation was, in fact, shown to occur within the Tyr 573 of the intracellular domain of MT1-MMP where it was suggested to affect endothelial cell migration (40). Impaired phosphorylation of Tyr 573 was shown to reduce tumor growth in mice (18), but further transcription studies were not performed. In our study, we demonstrate that impaired Tyr 573 phosphorylation abrogates the ability of MT1-MMP to regulate CSF-2 and CSF-3 gene transcription which may, in part, explain the previously reported low tumor-associated angiogenesis.…”

Matrix metalloproteinases in tumorigenesis: an evolving paradigm

“…However, MMP-9 promotes retinal ganglion cell death after optic nerve ligation [89]. MT1-MMP downregulates the glucose-6-phosphate transporter expression and promotes bone marrow stromal cell death [90]. Active stromelysin-3 (MMP-11), but not the inactive MMP-11, increases MCF-7 survival in three-dimensional Matrigel culture via activation of p42/p44 MAP-kinase and Akt [91].…”

Matrix Metalloproteinases in Venous Tissue Remodeling and Varicose Vein Formation

“…Other tumor cell lines such as human chondrosarcoma have shown decreased tumor invasion of type I collagen matrix in vitro by siRNA directed inhibition of MMP-1 [145]. Gene silencing using siRNA targeted for MT1-MMP to reduce activation of proMMP-2 in bone marrow derived stromal cells attenuated the induction of cell necrosis [146]. The use of siRNA allows for precise and specific gene knockdown and removes the potential for non-specific inhibition by longer double stranded antisense RNAs.…”