Differential Regulation of Membrane Type 1-Matrix Metalloproteinase Activity by ERK 1/2- and p38 MAPK-modulated Tissue Inhibitor of Metalloproteinases 2 Expression Controls Transforming Growth Factor-β1-induced Pericellular Collagenolysis

Munshi, Hidayatullah G.; Wu, Yi; Mukhopadhyay, Santanu; Ottaviano, Adam J.; Sassano, Antonella; Koblinski, Jennifer E.; Platanias, Leonidas C.; Stack, M. Sharon

doi:10.1074/jbc.m404958200

Cited by 138 publications

(121 citation statements)

References 70 publications

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“…GCM rapidly up-regulated microglial MT1-MMP expression and activity. Induction of MT1-MMP depended on TLR signaling (via the TLR adaptor MyD88) and activation of the p38 MAPK pathway, which is in agreement with studies showing that p38 MAPK activation is induced downstream of TLR and MyD88 signaling (12) and that MT1-MMP expression is regulated through p38 MAPK (13,14).…”

Section: Glioma Cells Induce Microglial Mt1-mmp Expression Via Tlr Sisupporting

confidence: 76%

“…Recent reports indicate that the p38 MAPK pathway is activated downstream of TLR and MyD88 signaling (12) and that MT1-MMP expression is triggered by p38 MAPK activity (13,14). To test if the p38 MAPK was activated by GCM, we analyzed microglial lysates by Western blotting with antibodies that selectively recognize the phosphorylated (i.e., activated) form of p38 MAPK.…”

Section: The Gcm-induced Mt1-mmp Expression and Activity In Microglia Ismentioning

confidence: 99%

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Gliomas induce and exploit microglial MT1-MMP expression for tumor expansion

Marković

Vinnakota

Chirasani

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

341

328

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for highly malignant gliomas (World Health Organization grade III and IV) there is no successful treatment; patients have an average survival time of approximately 1 y after diagnosis. Glioma cells are highly invasive and infiltrate normal brain tissue, and as a result, surgical resection is always incomplete. Degradation of ECM by membrane-bound and secreted metalloproteases facilitates glioma invasion. In particular, the membrane-bound metalloproteases are pivotal for tumor invasion as they very efficiently digest extracellular matrix proteins and also activate secreted metalloproteases (1) like matrix metalloproteinase-2 (MMP-2, also known as gelatinase A), which is one of the major proteases involved in glioma invasion in mouse models (2) and probably also in humans (3). Hence, membrane-inserted metalloproteases like membrane type 1 matrix metalloproteinase (MT1-MMP) can enable gliomas to invade the brain parenchyma as single cells (4).Microglia are the intrinsic immune cells of the brain; they control the innate and the adaptive immune response in the CNS and are activated by inflammatory or other pathological stimuli (5). Activation of microglial toll-like receptors (TLRs) triggers the innate immune response and can initiate host-defense and tissue repair mechanisms, but also CNS inflammation, neurodegeneration, and trauma (5, 6). As microglial cells are attracted toward glioma in large numbers-glioma tissue consists of as much as 30% microglial cells-and because microglia density in gliomas positively correlates with malignancy, invasiveness, and grading of the tumors (7-9), we investigated if microglia may actively contribute to glioma expansion. Here, we show that soluble factors released from glioma stimulate microglial TLRs, resulting in microglial MT1-MMP expression via the TLR downstream signaling molecules MyD88 and p38 MAPK. In turn, MT1-MMP expression and activity in these immune cells promotes glioma cell invasion and tumor expansion. ResultsGlioma Associated Microglia Over-Express MT1-MMP. We analyzed the expression pattern of the matrix protease MT1-MMP in mouse and human gliomas and found the enzyme to be expressed predominantly in microglial cells closely associated with the tumors. Whereas tumor-free human brain samples showed virtually no MT1-MMP expression, we detected intense MT1-MMP labeling, especially in higher-grade gliomas. Importantly, in human samples, immunolabeling for the microglial marker Iba1 and for MT1-MMP largely overlapped [supporting information (SI) Fig. S1 A-D and Table S1]. Likewise, after injection of a human glioma cell line (U373 cells) into immunodeficient mice, we detected that microglia represent the predominant cell type contributing intratumoral MT1-MMP expression (see Fig. S1E).In our in vivo mouse model, the glioma cells were identified by stable expression of EGFP and microglial cells by immunolabeling for Iba1. In sections obtained from mice 2 weeks after intracerebral injection with isogenic glioma cells (GL261 cells), we found an increased density of mic...

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Section: Glioma Cells Induce Microglial Mt1-mmp Expression Via Tlr Sisupporting

confidence: 76%

Section: The Gcm-induced Mt1-mmp Expression and Activity In Microglia Ismentioning

confidence: 99%

Gliomas induce and exploit microglial MT1-MMP expression for tumor expansion

Marković

Vinnakota

Chirasani

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

341

328

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“…In contrast to squamous cell carcinomas, glioma cells exhibited no regulation of p mitogen-activated protein kinase (MAPK)/p extracellular-related kinase (ERK) ( Table 1) to bridge the gap between survival pathways and regulation of MT1-MMP expression and hence invasiveness. 24 In contrast to the significant reduction of invasiveness, inhibiting TGF-b 2 or MMP-2 did not alter the sensitivity of control or BCL-x Linducible cells to CD95L/CHX-induced cell death, confirming two independent pathways to invasiveness or survival controlled by BCL-x L (Figure 6e). Previously, BCL-x L -induced downregulation of type 1 inositol 1,4,5-trisphosphate receptor had been linked to reduced T-cell antigen receptor ligationinduced Ca 2 þ flux in transgenic murine T cells and lower inositol 1,4,5-trisphosphate-mediated Ca 2 þ release capacity in microsomes.…”

Section: Discussionmentioning

confidence: 68%

BCL-xL: time-dependent dissociation between modulation of apoptosis and invasiveness in human malignant glioma cells

et al. 2005

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Conditionally BCL-x L -overexpressing LNT-229 Tet-On glioma cell clones were generated to investigate whether the 'antiapoptosis phenotype' and the 'motility phenotype' mediated by BCL-2 family proteins in glioma cells could be separated. BCL-x L induction led to an immediate and concentration-dependent protection of LNT-229 cells from apoptosis. BCL-x L induction for up to 3 days did not result in altered invasiveness. In contrast, long-term BCL-x L induction for 21 days resulted in increased transforming growth factorb 2 expression, and in metalloproteinase-2 and -14 dependent, but integrin independent, increased invasiveness. Withdrawal of doxycycline (Dox) abolished the protection from apoptosis whereas the 'invasion phenotype' remained stable. Dox stimulation of BCL-x L -inducible LNT-229 cells conferred infiltrative growth to BCL-x L -positive glioma cells in vivo and reduced the survival of tumor-bearing mice. These data allow to dissect a direct antiapoptotic action of BCL-x L from an indirect effect, presumably mediated by altered gene expression, which modifies tumor cell invasiveness in vitro and in vivo.

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“…SCC25 cells were obtained from American Type Culture Collection (29). SCC25 cells were routinely maintained in DMEM and Ham's F-12 medium (1:1) containing 10% fetal calf serum and supplemented with 100 units/ml penicillin and 100 g/ml streptomycin (4,30). OKF6 cells were maintained in keratinocyte-SFM supplemented with 100 units/ml penicillin, 100 g/ml streptomycin, 25 g/ml bovine pituitary extract (supplied with the medium), 0.2 ng/ml epidermal growth factor, and 0.31 mM CaCl 2 (31,32).…”

Section: Methodsmentioning

confidence: 99%

Rho-ROCK-Myosin Signaling Meditates Membrane Type 1 Matrix Metalloproteinase-induced Cellular Aggregation of Keratinocytes

Dangi-Garimella

Redig

Shields

et al. 2010

Journal of Biological Chemistry

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Matrix metalloproteinases (MMPs) 2 are a large family of highly conserved metalloendopeptidases with proteolytic activity directed against a variety of extracellular matrix (ECM) substrates (1-3). MMPs have been implicated in basement membrane proteolysis, activation of growth factors, and cleavage of cell-adhesion molecules. Extending mechanistic investigation to cancer biology, numerous studies have shown that MMP overexpression enhances the invasive activity of tumor cell lines (4 -6). Analysis of human disease further supports the pro-tumorigenic role of MMPs, as increased expression of these proteases in tumor samples is clinically associated with invasion, metastasis, poor prognosis, and shorter survival times (7,8). In the specific case of squamous cell carcinoma (SCC), increased expression of membrane type 1-MMP (MT1-MMP, MMP14) is associated with ECM breakdown, tissue invasion, and lymph node metastasis (8).However, several animal studies have now clearly demonstrated that multiple members of the MMP family provide a paradoxically protective effect during the relentless molecular destruction that characterizes malignant progression. MMPs may have been initially identified as potent pro-tumorigenic proteases, but their simultaneous ability to function in an opposing, anti-tumorigenic role is now equally well established (9, 10). Such data underscore both the complexity of MMP activity in cellular signaling events as well as the importance of stringently evaluating the context in which these proteases take on either an anti-tumorigenic or pro-tumorigenic role. Intriguingly, several recent studies using SCC models have begun to suggest a putative mechanism through which MMPs may be induced to function primarily as anti-tumorigenic proteases. When exposed to carcinogens, MMP3-null mice developed squamous cell skin cancers that not only grew faster but were also strikingly less differentiated than those of control animals (11). Significantly, orthotopic injection of MMP3-expressing tumor cells resulted in pronounced tumor cell differentiation (12). However, although such findings indicate that MMPs may inhibit SCC progression by promoting tumor cell differentiation, the precise mechanism through which these proteinases regulate this process has not yet been elucidated.In normal tissue keratinocyte differentiation is a complex process mediated by cell-ECM and cell-cell interactions that subsequently activate downstream signaling pathways (13-15). Specifically, among structural proteins, integrins mediate primarily cell-ECM interactions, whereas cadherins are responsible for cell-cell interactions (13). In vitro activation of integrins or inhibition of cadherins after ligation or dominant negative expression, respectively, results in negative regulation of human keratinocyte differentiation (16 -18). Furthermore, beyond structural proteins, Rho GTPases are also known to be an important component of keratinocyte differentiation pathways. Rho signaling has been shown to mediate cell-cell and cell-matrix adhesion...

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Differential Regulation of Membrane Type 1-Matrix Metalloproteinase Activity by ERK 1/2- and p38 MAPK-modulated Tissue Inhibitor of Metalloproteinases 2 Expression Controls Transforming Growth Factor-β1-induced Pericellular Collagenolysis

Cited by 138 publications

References 70 publications

Gliomas induce and exploit microglial MT1-MMP expression for tumor expansion

Gliomas induce and exploit microglial MT1-MMP expression for tumor expansion

BCL-xL: time-dependent dissociation between modulation of apoptosis and invasiveness in human malignant glioma cells

Rho-ROCK-Myosin Signaling Meditates Membrane Type 1 Matrix Metalloproteinase-induced Cellular Aggregation of Keratinocytes

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