Fluid Shear Stress and Sphingosine 1-Phosphate Activate Calpain to Promote Membrane Type 1 Matrix Metalloproteinase (MT1-MMP) Membrane Translocation and Endothelial Invasion into Three-dimensional Collagen Matrices

Kang, Hyojeung; Kwak, Hyo‐Bum; Kaunas, Roland; Bayless, Kayla J.

doi:10.1074/jbc.m111.290841

Cited by 47 publications

(65 citation statements)

References 62 publications

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“…Others have shown a role for mechanical regulation over MMP activity and invadopodia, which locally degrade ECM [10,11,12,32,33]. In addition, MMP-14 is known to cleave and activate MMP-2 [1].…”

Section: Resultsmentioning

confidence: 99%

Matrix metalloproteinase-14 is a mechanically regulated activator of secreted MMPs and invasion

Haage

Nam

et al. 2014

Biochemical and Biophysical Research Communications

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Matrix metalloproteinases (MMPs) are extracellular matrix (ECM) degrading enzymes and have complex and specific regulation networks. This includes activation interactions, where one MMP family member activates another. ECM degradation and MMP activation can be initiated by several different stimuli including changes in ECM mechanical properties or intracellular contractility. These mechanical stimuli are known enhancers of metastatic potential. MMP-14 facilitates local ECM degradation and is well known as a major mediator of cell migration, angiogenesis and invasion. Recently, function blocking antibodies have been developed to specifically block MMP-14, providing a useful tool for research as well as therapeutic applications. Here we utilize a selective MMP-14 function blocking antibody to delineate the role of MMP-14 as an activator of other MMPs in response to changes in cellular contractility and ECM stiffness. Inhibition using function blocking antibodies reveals that MMP-14 activates soluble MMPs like MMP-2 and -9 under various mechanical stimuli in the pancreatic cancer cell line, Panc-1. In addition, inhibition of MMP-14 abates Panc-1 cell extension into 3D gels to levels seen with non-specific pan-MMP inhibitors at higher concentrations. This strengthens the case for MMP function blocking antibodies as more potent and specific MMP inhibition therapeutics. (515) Keywords MT1-MMP

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Section: Resultsmentioning

confidence: 99%

Matrix metalloproteinase-14 is a mechanically regulated activator of secreted MMPs and invasion

Haage

Nam

et al. 2014

Biochemical and Biophysical Research Communications

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“…Previous cell-based experiments suggested that calpain proteolyzes focal adhesion proteins, 19 thereby facilitating cell motility 11 and subsequent angiogenic responses in ECs. 10,11 Present cancer allograft experiments suggested that EC-specific introduction of CAST exhibited reduction in vascular leakage, promotion of pericyte coverage, and formation of basement membrane in tumor neovessels, as well as had angiostatic effects (Figure 2). Similarly, the absence of pericyte coverage and the formation of vascular tufts in OIR lesions were abrogated by CAST introduction (Figure 3).…”

Section: Discussionmentioning

confidence: 99%

“…Previous investigations disclosed that calpain, a Ca 2+ -sensitive intracellular cysteine protease, exerts angiogenic effects on fluid shear stress-and VEGF-stimulated ECs based on the in vitro invasion assay 10 and in vitro tube formation assay, 11 respectively. Well-established ubiquitous isozymes, μ-and m-calpain, which require micromolar and millimolar levels of Ca 2+ for half-maximal activation, respectively, are normally kept inactive because an endogenous inhibitor, calpastatin (CAST), colocalizes and robustly downregulates their enzymatic activity intracellularly.…”

mentioning

confidence: 99%

Calpastatin Counteracts Pathological Angiogenesis by Inhibiting Suppressor of Cytokine Signaling 3 Degradation in Vascular Endothelial Cells

Miyazaki

Taketomi

Saito

et al. 2015

Circulation Research

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Rationale: Janus kinase/signal transducer and activator of transcription (JAK/STAT) signals and their endogenous inhibitor, suppressor of cytokine signaling 3 (SOCS3), in vascular endothelial cells (ECs) reportedly dominate the pathological angiogenesis. However, how these inflammatory signals are potentiated during pathological angiogenesis has not been fully elucidated. We suspected that an intracellular protease calpain, which composes the multifunctional proteolytic systems together with its endogenous inhibitor calpastatin (CAST), contributes to the JAK/STAT regulations. Objective: To specify the effect of EC calpain/CAST systems on JAK/STAT signals and their relationship with pathological angiogenesis. Methods and Results: The loss of CAST, which is ensured by several growth factor classes, was detectable in neovessels in murine allograft tumors, some human malignant tissues, and oxygen-induced retinopathy lesions in mice. EC-specific transgenic introduction of CAST caused downregulation of JAK/STAT signals, upregulation of SOCS3 expression, and depletion of vascular endothelial growth factor (VEGF)-C, thereby counteracting unstable pathological neovessels and disease progression in tumors and oxygen-induced retinopathy lesions in mice. Neutralizing antibody against VEGF-C ameliorated pathological angiogenesis in oxygen-induced retinopathy lesions. Small interfering RNA–based silencing of endogenous CAST in cultured ECs facilitated μ-calpain–induced proteolytic degradation of SOCS3, leading to VEGF-C production through amplified interleukin-6–driven STAT3 signals. Interleukin-6–induced angiogenic tube formation in cultured ECs was accelerated by CAST silencing, which is suppressible by pharmacological inhibition of JAK/STAT signals, antibody-based blockage of VEGF-C, and transfection of calpain-resistant SOCS3, whereas transfection of wild-type SOCS3 exhibited modest angiostatic effects. Conclusions: Loss of CAST in angiogenic ECs facilitates μ-calpain–induced SOCS3 degradation, which amplifies pathological angiogenesis through interleukin-6/STAT3/VEGF-C axis.

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“…1 and Table 1). It is likely that VEGF 35,36) and fluid shear stress 13,37,38) are representative activators of calpain systems in ECs under physiological conditions. ECs exhibit measurable calpain activity even under unstimulated conditions 39,40) , which may be due to spontaneous Ca 2＋ mobilization in the cells 41) .…”

Section: Calpain and Vascular Integritymentioning

confidence: 99%

“…Mechanistically, calpainmediated regulation of small GTPases 13,40) as well as calpain-induced proteolysis of focal adhesion proteins 37) during EC dynamics has been documented previously. Accordingly, calpain systems appear to play key roles in angiogenesis 36,38) , wound closure 39) and maintenance of barrier functions 13,40) in ECs. In addition to motility responses, it has been reported that nitric oxide (NO) production in ECs is modulated through calpain-induced proteolysis of HSP90 42) or calpain-regulated PI3K/AMPK signaling 35) .…”

Section: Calpain and Vascular Integritymentioning

confidence: 99%

Calpain and Atherosclerosis

Miyazaki

Koya

Kigawa

et al. 2013

JAT

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Fluid Shear Stress and Sphingosine 1-Phosphate Activate Calpain to Promote Membrane Type 1 Matrix Metalloproteinase (MT1-MMP) Membrane Translocation and Endothelial Invasion into Three-dimensional Collagen Matrices

Cited by 47 publications

References 62 publications

Matrix metalloproteinase-14 is a mechanically regulated activator of secreted MMPs and invasion

Matrix metalloproteinase-14 is a mechanically regulated activator of secreted MMPs and invasion

Calpastatin Counteracts Pathological Angiogenesis by Inhibiting Suppressor of Cytokine Signaling 3 Degradation in Vascular Endothelial Cells

Calpain and Atherosclerosis

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