Matrix Metalloproteinase 1 Interacts with Neuronal Integrins and Stimulates Dephosphorylation of Akt

Johns Hopkins University, Baltimore, Maryland, United States
Journal of Biological Chemistry (Impact Factor: 4.57). 03/2004; 279(9):8056-62. DOI: 10.1074/jbc.M307051200
Source: PubMed


Several studies have demonstrated that matrix metalloproteinases (MMPs) are cytotoxic. The responsible mechanisms, however,
are not well understood. MMPs may promote cytotoxicity through their ability to disrupt or degrade matrix proteins that support
cell survival, and MMPs may also cleave substrates to generate molecules that stimulate cell death. In addition, MMPs may
themselves act on cell surface receptors that affect cell survival. Among such receptors is the α2β1 integrin, a complex that has previously been linked to leukocyte death. In the present study we show that human neurons express
α2β1 and that pro-MMP-1 interacts with this integrin complex. We also show that stimulation of neuronal cultures with MMP-1 is
associated with a rapid reduction in the phosphorylation of Akt, a kinase that can influence caspase activity and cell survival.
Moreover, MMP-1-associated dephosphorylation of Akt is inhibited by a blocking antibody to the α2 integrin, but not by batimastat, an inhibitor of MMP-1 enzymatic activity. Such dephosphorylation is also stimulated by a
catalytic mutant of pro-MMP-1. Additional studies show that MMP-1 causes neuronal death, which is significantly diminished
by both a general caspase inhibitor and anti-α2 but not by batimastat. Together, these results suggest that MMP-1 can stimulate dephosphorylation of Akt and neuronal death
through a non-proteolytic mechanism that involves changes in integrin signaling.

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    • "Western blots reveal a single band of the expected size (e.g. P4C10: van der Pluijm et al., 2001; N29: Conant et al., 2004), an epitope has been mapped in β1-integrin (P4C10: Takada and Puzon, 1993), and functions known to require β1-integrins can be blocked (e.g. (P4C10: Carter et al., 1990; Nagy et al, 2006) or enhanced (N29: Wilkins et al, 1996). "
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    ABSTRACT: β1-containing integrins are required for persistent synaptic potentiation in hippocampus and regulate hippocampal-dependent learning. Based largely on indirect evidence, there is a prevailing assumption that β1-integrins are localized at synapses, where they contribute to synapse adhesion and signaling, but this has not been examined directly. Here we investigate the fine localization of β1-integrin in adult mouse hippocampus using high-resolution immunogold labeling, with a particular emphasis on synaptic labeling patterns. We find that β1-integrins localize to synapses in CA1 and are concentrated postsynaptically. At the postsynaptic membrane, β1-integrins are found more commonly clustered near active zone centers rather than at the peripheral edges. In mice harboring a conditional deletion of β1-integrins, labeling for N-cadherin and neuroligins increases. Western blots show increased levels of N-cadherin in total lysates and neuroligins increase selectively in synaptosomes. These data suggest there is a dynamic, compensatory adjustment of synaptic adhesion. Such adjustment is specific only for certain cell adhesion molecules (CAMs), because labeling for SynCAM is unchanged. Together, our findings demonstrate unequivocally that β1-integrin is an integral synaptic adhesion protein, and suggest that adhesive function at the synapse reflects a cooperative and dynamic network of multiple CAM families.
    Full-text · Article · Jun 2012 · The Journal of Comparative Neurology
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    • "Matrix metalloproteinase-1 (MMP-1) plays a role in tissue remodeling during development, inflammation, migration of inflammatory and malignant cells, and COPD and emphysema patho genesis (Segura-Valdez et al. 2000). It also has neuro tropic effects, possibly enhancing sensitization of airway-innervating sensory neurons , contributing to airway hypersensitization and chronic cough (Conant et al. 2004). We recently identified a novel pathway that results in DEP-induced MMP‑1 activation and entails activation of RAS-RAF-MEK-extracellular signal–regulated kinase (ERK) signaling, dependent on β-arrestins (Li et al. 2009). "
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    ABSTRACT: Human respiratory epithelia function in airway mucociliary clearance and barrier function and have recently been implicated in sensory functions. We investigated a link between chronic obstructive pulmonary disease (COPD) pathogenesis and molecular mechanisms underlying Ca2+ influx into human airway epithelia elicited by diesel exhaust particles (DEP). Using primary cultures of human respiratory epithelial (HRE) cells, we determined that these cells possess proteolytic signaling machinery, whereby proteinase-activated receptor-2 (PAR-2) activates Ca2+-permeable TRPV4, which leads to activation of human respiratory disease-enhancing matrix metalloproteinase-1 (MMP-1), a signaling cascade initiated by diesel exhaust particles (DEP), a globally relevant air pollutant. Moreover, we observed ciliary expression of PAR-2, TRPV4, and phospholipase-Cβ3 in human airway epithelia and their DEP-enhanced protein-protein complex formation. We also found that the chronic obstructive pulmonary disease (COPD)-predisposing TRPV4P19S variant enhances Ca2+ influx and MMP 1 activation, providing mechanistic linkage between man-made air pollution and human airway disease. DEP evoked protracted Ca2+ influx via TRPV4, enhanced by the COPD-predisposing human genetic polymorphism TRPV4P19S. This mechanism reprograms maladaptive inflammatory and extracellular-matrix-remodeling responses in human airways. The novel concept of air pollution-responsive ciliary signal transduction from PAR-2 to TRPV4 in human respiratory epithelia will accelerate rationally targeted therapies, possibly via the inhalatory route.
    Full-text · Article · Jan 2011 · Environmental Health Perspectives
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    • "Western blot was later performed for ICAM-5 (a) or, as an additional control, b 1 (b). ICAM-5 treatment of cells and immunoprecipitation was performed as previously described for MMP-1 (Conant et al. 2004). To determine whether ICAM-5 might interact with b 1 in vivo, we also performed studies using lysate from MA treated (6 h) murine hippocampus . "
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    ABSTRACT: J. Neurochem. (2011) 118, 521–532. Methamphetamine (MA) is a highly addictive psychostimulant that, used in excess, may be neurotoxic. Although the mechanisms that underlie its addictive potential are not completely understood, in animal models matrix metalloproteinase (MMP) inhibitors can reduce behavioral correlates of addiction. In addition, evidence from genome-wide association studies suggests that polymorphisms in synaptic cell-adhesion molecules (CAMs), known MMP substrates, are linked to addictive potential in humans. In the present study, we examined the ability of MA to stimulate cleavage of intercellular adhesion molecule-5 (ICAM-5), a synaptic CAM expressed on dendritic spines in the telencephalon. Previous studies have shown that shedding of ICAM-5 is associated with maturation of dendritic spines, and that MMP-dependent shedding occurs with long term potentiation. Herein, we show that MA stimulates ectodomain cleavage of ICAM-5 in vitro, and that this is abrogated by a broad spectrum MMP inhibitor. We also show that an acute dose of MA, administered in vivo, is associated with cleavage of ICAM-5 in murine hippocampus and striatum. This occurs within 6 h and is accompanied by an increase in MMP-9 protein. In related experiments, we examined the potential consequences of ICAM-5 shedding. We demonstrate that the ICAM-5 ectodomain can interact with β1 integrins, and that it can stimulate β1 integrin-dependent phosphorylation of cofilin, an event that has previously been linked to MMP-dependent spine maturation. Together these data support an emerging appreciation of MMPs as effectors of synaptic plasticity and suggest a mechanism by which MA may influence the same.
    Full-text · Article · Dec 2010 · Journal of Neurochemistry
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