Potassium Channel Modulation by A Toxin Domain in Matrix Metalloprotease 23

Rangaraju, Srikant; Khoo, Keith K.; Feng, Zhiping; Crossley, George H.; Nugent, Daniel; Khaytin, Ilya; Pennington, Michael W.; Norton, Raymond S.; Chandy, K. George

doi:10.1016/j.bpj.2009.12.1145

Cited by 8 publications

(16 citation statements)

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“…The residual K V 1.3 currents in MMP23-FLand MMP23-PD-expressing cells exhibited the same biophysical properties as wild-type K V 1.3. Because MMP23 is not present in the surface membrane (6,7,10), it is likely that these channels are not associated with MMP23-FL or MMP23-PD. MMP23-FL and MMP23-PD both co-localized with the ER marker YFP-Stim-1, confirming earlier studies reporting that mouse, rat, and human MMP23 are ER proteins (6,7,10).…”

Section: Discussionmentioning

confidence: 99%

“…This result suggests that MMP23-FL decreases the number of functional K V 1.3 channels on the cell surface but does not alter the properties of the channel. Because MMP23-FL has not been detected in the plasma membrane (6,7,10), it is possible that the K V 1.3 channels on the surface of MMP23-FL-expressing cells are not associated, directly or indirectly, with MMP23-FL and may represent channels that have escaped from an intracellular pool.…”

Section: The Prodomain Of Mmp23 (Mmp23-pd) Selectively Suppresses K Vmentioning

confidence: 99%

“…C-terminally tagged mouse, rat, and human MMP23 all localize to perinuclear regions and the ER in mammalian cells (6,7). N-terminally GFP-tagged rat MMP23-FL also co-localizes with the ER marker sarcoplasmic reticulum Ca 2ϩ -ATPase (SERCA) (10). Corroborating the published data, N-terminally DsRed-tagged MMP23-FL and MMP23-PD both co-localized with the ER marker YFP-Stim-1 in COS-7 cells (Fig.…”

Section: The Prodomain Of Mmp23 (Mmp23-pd) Selectively Suppresses K Vmentioning

confidence: 99%

“…We reported previously a novel channel-modulating, metalloprotease-independent, function for MMP23 (10). Full-length MMP23 zymogen suppresses voltage-gated K V 1.3 and K V 1.6 potassium channels by intracellular retention, but has no effect on related K V 1 channels (e.g.…”

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confidence: 99%

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Intracellular Trafficking of the KV1.3 Potassium Channel Is Regulated by the Prodomain of a Matrix Metalloprotease

Nguyen¹,

Galea

Schmunk³

et al. 2013

Journal of Biological Chemistry

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Background: Noncanonical functions of matrix metalloproteases are poorly characterized. Results: The prodomain of MMP23 co-localizes with and traps K V 1.3 channels intracellularly, thereby suppressing K V 1.3 currents. Conclusion: A novel metalloprotease-independent channel-modulating function of the MMP23 prodomain has been identified. Significance: The topological similarity of the prodomain of MMP23 and KCNE proteins suggests a shared mechanism of channel modulation.

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Section: Discussionmentioning

confidence: 99%

Section: The Prodomain Of Mmp23 (Mmp23-pd) Selectively Suppresses K Vmentioning

confidence: 99%

Section: The Prodomain Of Mmp23 (Mmp23-pd) Selectively Suppresses K Vmentioning

confidence: 99%

mentioning

confidence: 99%

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Intracellular Trafficking of the KV1.3 Potassium Channel Is Regulated by the Prodomain of a Matrix Metalloprotease

Nguyen¹,

Galea

Schmunk³

et al. 2013

Journal of Biological Chemistry

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“…Part of the neurotoxicity of the venom is likely due to the abovementioned proteins containing ShK domains (Hwang et al, 2007, Rangaraju et al, 2010 as well as to neurotoxic PLA2s. Additional toxins, for example a large (> 100 kDa) neurotoxin (which potentially also has cytolytic activity), are known to be found in the venom Weber, 1991, Klug et al, 1989a) but await identification and characterization.…”

Section: How Does Hydra Paralyse Its Prey Without Using Peptide Neuromentioning

confidence: 99%

What Hydra can teach us about chemical ecology how a simple, soft organism survives in a hostile aqueous environment

Rachamim

Sher

2012

Int. J. Dev. Biol.

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Hydra and its fellow cnidarians -sea anemones, corals and jellyfish -are simple, mostly sessile animals that depend on bioactive chemicals for survival. In this review, we briefly describe what is known about the chemical armament of Hydra, and detail future research directions where Hydra can help illuminate major questions in chemical ecology, pharmacology, developmental biology and evolution. Focusing on two groups of putative toxins from Hydra -phospholipase A2s and proteins containing ShK and zinc metalloprotease domains, we ask: how do different venom components act together during prey paralysis? How is a venom arsenal created and how does it evolve? How is the chemical arsenal delivered to its target? To what extent does a chemical and biotic coupling exist between an organism and its environment? We propose a model whereby in Hydra and other cnidarians, bioactive compounds are secreted both as localized point sources (nematocyte discharges) and across extensive body surfaces, likely combining to create complex "chemical landscapes". We speculate that these cnidarian-derived chemical landscapes may affect the surrounding community on scales from microns to, in the case of coral reefs, hundreds of kilometers.

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Therapeutic Potential of Matrix Metalloproteinase Inhibition in Breast Cancer

Radisky

Raeeszadeh‐Sarmazdeh

Radisky

2017

J of Cellular Biochemistry

107

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Matrix metalloproteinases (MMPs) are a family of zinc endopeptidases that cleave nearly all components of the extracellular matrix as well as many other soluble and cell-associated proteins. MMPs have been implicated in normal physiological processes, including development, and in the acquisition and progression of the malignant phenotype. Disappointing results from a series of clinical trials testing small molecule, broad spectrum MMP inhibitors as cancer therapeutics led to a re-evaluation of how MMPs function in the tumor microenvironment, and ongoing research continues to reveal that these proteins play complex roles in cancer development and progression. It is now clear that effective targeting of MMPs for therapeutic benefit will require selective inhibition of specific MMPs. Here, we provide an overview of the MMP family and its biological regulators, the tissue inhibitors of metalloproteinases (TIMPs). We then summarize recent research from model systems that elucidate how specific MMPs drive the malignant phenotype of breast cancer cells, including acquisition of cancer stem cell features and induction of the epithelial-mesenchymal transition, and we also outline clinical studies that implicate specific MMPs in breast cancer outcomes. We conclude by discussing ongoing strategies for development of inhibitors with therapeutic potential that are capable of selectively targeting the MMPs most responsible for tumor promotion, with special consideration of the potential of biologics including antibodies and engineered proteins based on the TIMP scaffold.

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Potassium Channel Modulation by A Toxin Domain in Matrix Metalloprotease 23

Cited by 8 publications

References 0 publications

Intracellular Trafficking of the KV1.3 Potassium Channel Is Regulated by the Prodomain of a Matrix Metalloprotease

Intracellular Trafficking of the KV1.3 Potassium Channel Is Regulated by the Prodomain of a Matrix Metalloprotease

What Hydra can teach us about chemical ecology how a simple, soft organism survives in a hostile aqueous environment

Therapeutic Potential of Matrix Metalloproteinase Inhibition in Breast Cancer

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