Calpain cleavage within dysferlin exon 40a releases a synaptotagmin-like module for membrane repair

Redpath, Gregory; Woolger, Natalie; Piper, Ann-Katrin; Lemckert, Fa A.; Lek, Angela; Greer, P.A.; North, Klaus; Cooper, Sandra T.

doi:10.1091/mbc.e14-04-0947

Cited by 64 publications

(109 citation statements)

References 35 publications

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“…Indeed, we found significant increases in full-length dysferlin protein, as detected with both Romeo (N-terminal) and Hamlet (C-terminal) monoclonal antibodies to dysferlin, in CAT-1041-treated quadriceps ( Figure 7, C and D). The C72 C-terminal cleavage product (25,26) was also increased with treatment, suggesting active membrane repair was enhanced in treated mice. While total Dysf gene expression was nearly 2-fold higher in treated mice ( Figure 7E), expression of the canonical (calcium sensitive) C2A isoform of Dysf was significantly reduced.…”

Section: Resultsmentioning

confidence: 95%

Disease-modifying effects of orally bioavailable NF-κB inhibitors in dystrophin-deficient muscle

Hammers¹,

Sleeper

Forbes

et al. 2016

JCI Insight

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Section: Resultsmentioning

confidence: 95%

Disease-modifying effects of orally bioavailable NF-κB inhibitors in dystrophin-deficient muscle

Hammers¹,

Sleeper

Forbes

et al. 2016

JCI Insight

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“…Myoferlin is a substrate for calpain whose enzymatic cleavage gives rise to a synaptotagmin-like module. 35 Interestingly, synaptotagmin is a protein involved in Ca 21 -triggered exocytosis, 36 suggesting a potential role for the cleavage fragment of myoferlin in exocytosis. Finally, myoferlin has been considered as a regulator of protein secretion by breast cancer cells.…”

Section: Discussionmentioning

confidence: 99%

Myoferlin plays a key role in VEGFA secretion and impacts tumor‐associated angiogenesis in human pancreas cancer

Fahmy

Gonzalez

Arafa

et al. 2015

Intl Journal of Cancer

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Pancreatic ductal adenocarcinoma is one of the most deadly forms of cancers with no satisfactory treatment to date. Recent studies have identified myoferlin, a ferlin family member, in human pancreas adenocarcinoma where its expression was associated to a bad prognosis. However, the function of myoferlin in pancreas adenocarcinoma has not been reported. In other cell types, myoferlin is involved in several key plasma membrane processes such as fusion, repair, endocytosis and tyrosine kinase receptor activity. In this study, we showed that myoferlin silencing in BxPC-3 human pancreatic cancer cells resulted in the inhibition of cell proliferation in vitro and in a significant reduction of the tumor volume in chick chorioallantoic membrane assay. In addition to be smaller, the tumors formed by the myoferlin-silenced cells showed a marked absence of functional blood vessels. We further demonstrated that this effect was due, at least in part, to an inhibition of VEGFA secretion by BxPC-3 myoferlin-silenced cells. Using immunofluorescence and electron microscopy, we linked the decreased VEGFA secretion to an impairment of VEGFA exocytosis. The clinical relevance of our results was further strengthened by a significant correlation between myoferlin expression in a series of human pancreatic malignant lesions and their angiogenic status evaluated by the determination of the blood vessel density.

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“…Caveolae have long been known to laten in response to mechanically induced membrane deformation stretch [3 ]. Indeed, the preincubation of cells with methyl-β-cyclodextrin diminishes the time to cell lysis upon hypotonic challenge [38]. Methyl-β-cyclodextrin is a cholesterol-depleting compound that has also been shown to severely reduce the number of caveolae at the cell surface [3 ], probably by limiting the recruitment of caveolin oligomers to the plasma membrane.…”

Section: Caveolae-mediated Decrease Of In-plane Membrane Tensionmentioning

confidence: 99%

“…However, a study of human myoblasts by Lek et al [50] led to the discovery that a calpain-cleaved product of dysferlin played a direct role in the sarcolemma's exocytic repair mechanism. "riely, calpains activated by injury-induced Ca + inlux cleave dysferlin, which releases its C-term fragment mini-dysferlinC [50,38,3 ]. Following vesicle packaging, mini-dysferlinCcontaining cytoplasmic vesicles are then transported to the wound site.…”

Section: Muscle Cells Dysferlin-mediated Exocytosismentioning

confidence: 99%

See 1 more Smart Citation

How Plasma Membrane and Cytoskeletal Dynamics Influence Single-Cell Wound Healing: Mechanotransduction, Tension and Tensegrity

Boucher¹,

Kato²,

Mandato³

2016

Wound Healing - New Insights Into Ancient Challenges

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Organisms are able to recover from injuries by replacing damaged tissues, which recover by replacing damaged cells and extracellular structures. Similarly, a cell recovers from injuries by replacing damaged components of its structural integrity its plasma membrane and cytoskeletal structures. Cells can be thought of as tensegral structures, their structural integrity relying on the interplay between tensile forces generated within and without the cell, and the compressive elements that counteracts them. "s such, direct or indirect insults to the plasma membrane or cytoskeleton of a cell may not only result in the temporary loss of structural integrity, but also directly impact its ability to respond to its environment. This chapter will focus on the various aspects linking tensile forces and single-cell wound healing where and how are they generated, how does the cell counteract them and how does the cell return to its previous tensegrity state? These questions will be explored using ubiquitous and cell-type speciic examples of singlecell repair processes. Special atention will be given to changes in plasma membrane composition and area to cytoskeletal dynamics, and how these factor each other to inluence and efect single-cell repair.

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Calpain cleavage within dysferlin exon 40a releases a synaptotagmin-like module for membrane repair

Cited by 64 publications

References 35 publications

Disease-modifying effects of orally bioavailable NF-κB inhibitors in dystrophin-deficient muscle

Disease-modifying effects of orally bioavailable NF-κB inhibitors in dystrophin-deficient muscle

Myoferlin plays a key role in VEGFA secretion and impacts tumor‐associated angiogenesis in human pancreas cancer

How Plasma Membrane and Cytoskeletal Dynamics Influence Single-Cell Wound Healing: Mechanotransduction, Tension and Tensegrity

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