LRP-1: A Checkpoint for the Extracellular Matrix Proteolysis

Etique, Nicolas; Verzeaux, Laurie; Dedieu, Stéphane; Emonard, Hervé

doi:10.1155/2013/152163

Cited by 76 publications

(57 citation statements)

References 83 publications

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“…Consistent with this, cholesterol is essential for molting in C. elegans (Yochem et al 1999;Merris et al 2003;Entchev and Kurzchalia 2005;Roudier et al 2005). In addition, studies on mammalian megalin suggest that C. elegans LRP-1 could promote molting in part by regulating the uptake of proteases and protease inhibitors (May et al 2007;Marzolo and Farfan 2011;Etique et al 2013). In addition to LRP-1, several other genes required for molting also affect intracellular trafficking and sterol-LRP-1 uptake including dab-1/Disabled, hgrs-1/VPS27, and sec-23/ SEC23 (Kamikura and Cooper 2003;Roberts et al 2003;Roudier et al 2005;Holmes et al 2007;Yochem et al 2015).…”

Section: Discussionmentioning

confidence: 89%

Conserved Ankyrin Repeat Proteins and Their NIMA Kinase Partners Regulate Extracellular Matrix Remodeling and Intracellular Trafficking inCaenorhabditis elegans

Lažetić¹,

Fay

2017

Genetics

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Molting is an essential developmental process in nematodes during which the epidermal apical extracellular matrix, the cuticle, is remodeled to accommodate further growth. Using genetic approaches, we identified a requirement for three conserved ankyrin repeat-rich proteins, MLT-2/ANKS6, MLT-3/ANKS3, and MLT-4/INVS, in Caenorhabditis elegans molting. Loss of mlt function resulted in severe defects in the ability of larvae to shed old cuticle and led to developmental arrest. Genetic analyses demonstrated that MLT proteins functionally cooperate with the conserved NIMA kinase family members NEKL-2/NEK8 and NEKL-3/NEK6/NEK7 to promote cuticle shedding. MLT and NEKL proteins were specifically required within the hyp7 epidermal syncytium, and fluorescently tagged mlt and nekl alleles were expressed in puncta within this tissue. Expression studies further showed that NEKL-2-MLT-2-MLT-4 and NEKL-3-MLT-3 colocalize within largely distinct assemblies of apical foci. MLT-2 and MLT-4 were required for the normal accumulation of NEKL-2 at the hyp7-seam cell boundary, and loss of mlt-2 caused abnormal nuclear accumulation of NEKL-2. Correspondingly, MLT-3, which bound directly to NEKL-3, prevented NEKL-3 nuclear localization, supporting the model that MLT proteins may serve as molecular scaffolds for NEKL kinases. Our studies additionally showed that the NEKL-MLT network regulates early steps in clathrin-mediated endocytosis at the apical surface of hyp7, which may in part account for molting defects observed in nekl and mlt mutants. This study has thus identified a conserved NEKL-MLT protein network that regulates remodeling of the apical extracellular matrix and intracellular trafficking, functions that may be conserved across species.KEYWORDS C. elegans; molting; NIMA kinase; endocytosis; ankyrin repeat proteins M OLTING is a ubiquitous process in nematode species, including Caenorhabditis elegans, and is required for organismal growth and development. Although the observable biomechanics and major morphological features of C. elegans molting were first described nearly 40 years ago (Hirsh et al. 1976;Singh and Sulston 1978), the molecular and cellular mechanisms underlying this complex process are largely unknown. Notably, molting occurs in both pathogenic and nonpathogenic nematode species, and molting factors have been proposed as potential targets for antiparasitic drugs (Page et al. 2014;Gooyit et al. 2015).Mechanistically, molting is the process by which nematodes remodel their epidermal apical extracellular matrix (ECM), termed the cuticle. In C. elegans larvae and adults, the cuticle serves as a mechanical barrier and provides physical and chemical protection from the environment (Page and Johnstone 2007). In addition, similar to the chitin-based exoskeleton of insects and other arthropods, the cuticle is required to facilitate organismal movement in conjunction with attached underlying muscles. Unlike arthropods, however, in nematodes the cuticle is comprised primarily of collagens (Page and Johnstone 20...

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Section: Discussionmentioning

confidence: 89%

Conserved Ankyrin Repeat Proteins and Their NIMA Kinase Partners Regulate Extracellular Matrix Remodeling and Intracellular Trafficking inCaenorhabditis elegans

Lažetić¹,

Fay

2017

Genetics

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“…LRP1 is involved in various biological processes such as lipoprotein metabolism and cell motility, and pathologically in neurodegenerative diseases, atherosclerosis and cancer [113] . LRP is a multifunctional cell surface receptor of more than 600 kDa in size with a single transmembrane-spanning domain.…”

Section: Low-density Lipoprotein Receptor-related Protein (Lrp)mentioning

confidence: 99%

Amyloid beta: structure, biology and structure-based therapeutic development

et al. 2017

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Amyloid beta peptide (Aβ) is produced through the proteolytic processing of a transmembrane protein, amyloid precursor protein (APP), by β-and γ-secretases. Aβ accumulation in the brain is proposed to be an early toxic event in the pathogenesis of Alzheimer's disease, which is the most common form of dementia associated with plaques and tangles in the brain. Currently, it is unclear what the physiological and pathological forms of Aβ are and by what mechanism Aβ causes dementia. Moreover, there are no efficient drugs to stop or reverse the progression of Alzheimer's disease. In this paper, we review the structures, biological functions, and neurotoxicity role of Aβ. We also discuss the potential receptors that interact with Aβ and mediate Aβ intake, clearance, and metabolism. Additionally, we summarize the therapeutic developments and recent advances of different strategies for treating Alzheimer's disease. Finally, we will report on the progress in searching for novel, potentially effective agents as well as selected promising strategies for the treatment of Alzheimer's disease. These prospects include agents acting on Aβ, its receptors and tau protein, such as small molecules, vaccines and antibodies against Aβ; inhibitors or modulators of β-and γ-secretase; Aβ-degrading proteases; tau protein inhibitors and vaccines; amyloid dyes and microRNAs.

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“…While investigation initially focused upon cholesterol transport, the roles of the LDL receptor-related proteins in embryonic development, Wnt signaling, and adult homeostasis have increasingly occupied centre stage. Low density lipoprotein receptor-related proteins (LRPs) are a group of transmembrane receptors involved in apolipoprotein binding, Wnt signaling, and human diseases [6, 7]. LRP - 5 and - 6 (LRP5 and LRP6) are two such receptors with specific patient mutations leading to metabolic dysregulation, elevated serum LDL and triglycerides (TGs), atherosclerosis, and high or low bone mass phenotypes [8–10].…”

Section: Introductionmentioning

confidence: 99%

Wnt signaling in cardiovascular disease: opportunities and challenges

Towler¹

2017

Current Opinion in Lipidology

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Purpose of review Cardiometabolic diseases increasingly afflict our aging, dysmetabolic citizenry. Complex signals regulating low density lipoprotein receptor-related protein (LRP) and frizzled protein family members – the plasma membrane receptors for the cadre of Wnt polypeptide morphogens – contribute to the control of cardiovascular homeostasis. Recent findings Both canonical (β-catenin-dependent) and noncanonical (β-catenin-independent) Wnt signaling programs control vascular smooth muscle cell (VSM) phenotypic modulation in cardiometabolic disease. LRP6 limits VSM proliferation, reduces arteriosclerotic transcriptional reprogramming, and preserves insulin sensitivity while LRP5 restrains foam cell formation. Adipose, skeletal muscle, macrophages and VSM have emerged as important sources of circulating Wnt ligands that are dynamically regulated during the prediabetes-diabetes transition with cardiometabolic consequences. Platelets release Dkk1, an LRP5/LRP6 inhibitor that induces endothelial inflammation and the prosclerotic endothelial-mesenchymal transition. By contrast, inhibitory secreted frizzled-related proteins shape the Wnt signaling milieu to limit myocardial inflammation with ischemia-reperfusion injury. VSM sclerostin, an inhibitor of canonical Wnt signaling in bone, restrains remodeling that predisposes to aneurysm formation, and is down-regulated in aneurysmal vessels by epigenetic methylation. Summary Components of the Wnt signaling cascade represent novel targets for pharmacological intervention in cardiometabolic disease. Conversely, strategies targeting the Wnt signaling cascade for other therapeutic purposes will have cardiovascular consequences that must be delineated to establish clinically useful pharmacokinetic – pharmacodynamic relationships.

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LRP-1: A Checkpoint for the Extracellular Matrix Proteolysis

Cited by 76 publications

References 83 publications

Conserved Ankyrin Repeat Proteins and Their NIMA Kinase Partners Regulate Extracellular Matrix Remodeling and Intracellular Trafficking inCaenorhabditis elegans

Conserved Ankyrin Repeat Proteins and Their NIMA Kinase Partners Regulate Extracellular Matrix Remodeling and Intracellular Trafficking inCaenorhabditis elegans

Amyloid beta: structure, biology and structure-based therapeutic development

Wnt signaling in cardiovascular disease: opportunities and challenges

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