Lipoprotein receptors and a Disabled family cytoplasmic adaptor protein regulate EGL-17/FGF export in <i>C. elegans</i>

Kamikura, Darren M.; Cooper, Jonathan A.

doi:10.1101/gad.1136103

Cited by 43 publications

(58 citation statements)

References 61 publications

(73 reference statements)

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“…However, a more recent study indicates that the mutations in Disabled were incorrectly mapped in the prior study (35), and thus the Disabled mutant phenotype in Drosophila is not known. In Caenorhabditis elegans, the Disabled ortholog was shown to coordinate selection of lipoprotein-related receptors and cargos in the secretory trafficking pathway and the mutant is deficient in efficient secretion of proteins, including the C. elegans fibroblast growth factor (36). Thus, it appears that the function of the Disabled protein is evolutionarily conserved between mammals and nematodes in its interaction with the lipoprotein-receptor family and other cell surface glycoproteins and trafficking of associated cargos to the cell surface.…”

Section: Discussionmentioning

confidence: 99%

Disabled-2 Is an Epithelial Surface Positioning Gene

Yang¹,

Cai

Roland

et al. 2007

Journal of Biological Chemistry

116

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The formation of the primitive endoderm layer on the surface of the inner cell mass is one of the earliest epithelial morphogenesis in mammalian embryos. In mouse embryos deficient of Disabled-2 (Dab2), the primitive endoderm cells lose the ability to position on the surface, resulting in defective morphogenesis. Embryonic stem cells lacking Dab2 are also unable to position on the surface of cell aggregates and fail to form a primitive endoderm outer layer in the embryoid bodies. The cellular function of Dab2, a cargo-selective adaptor, in mediating endocytic trafficking of clathrin-coated vesicles is well established. We show here that Dab2 mediates directional trafficking and polarized distribution of cell surface proteins such as megalin and E-cadherin and propose that loss of polarity is the underlying mechanism for the loss of epithelial cell surface positioning in Dab2-deficient embryos and embryoid bodies. Thus, the findings indicate that Dab2 is a surface positioning gene and suggest a novel mechanism of epithelial cell surface targeting.Epithelial cells are positioned on the outer surface of organs or the inner surface of glandular structures and are involved in diverse physiological functions. Simple epithelia consist of monolayered cells that form a sheet through cell-cell adherens junctions and attach to a basement membrane that lies underneath (1). Epithelial cells are polarized with the apical surface exposed, or free from cell-cell contact and the basal side lying in contact with a basement membrane or stromal cells. The cellfree apical space and basal contact are unique hallmarks of an epithelium and are likely positioning cues for the surface localization of the epithelial cells (2), although the molecular details and genes critical for epithelial cell surface positioning are yet uncertain and undefined. The concept that cues are required for epithelial surface positioning is also reinforced by observations of the disorganized growth of carcinomas. Carcinoma cells can be viewed as epithelial cells that have lost their ability to perceive surface positioning cues, and the neoplastic cells no longer obey the constraint imposed by tissue organization (3).The early embryos of vertebrates, especially mammalian species, have great plasticity, and significant cell dispersal, movement, and migration occur before their final positioning and acquisition of cell fates (4). Shown in the classical cell sorting experiments by Townes and Holtfreter (5), early embryonic amphibian cells of epidermis, endoderm, mesoderm, and neural plate, if dispersed, are able to segregate spontaneously upon aggregation, indicating cell positioning is an autonomous property.The primitive endoderm of mammalian early embryos is the first typical epithelial cell type derived that is capable of producing a basement membrane (6). Recent understanding is that the primitive endoderm cells arise from the differentiation of the pluripotent cells of the inner cell mass and migrate out to the surface to form the primitive endoderm layer (7...

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Section: Discussionmentioning

confidence: 99%

Disabled-2 Is an Epithelial Surface Positioning Gene

Yang¹,

Cai

Roland

et al. 2007

Journal of Biological Chemistry

116

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“…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: 99%

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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“…Ce-DAB-1 is related to a disabled family of cytoplasmic adaptor proteins interacting with LRPs and regulating the endocytosis of megalin and lipoprotein receptors in mammals. Recently, unshed cuticle molting defects induced by Ce-dab-1 RNAi have been reported (45). Finally, Ce-LRP-1 is an ortholog of LRP-mammalian receptors and is suggested to be a close counterpart of megalin (34).…”

Section: Discussion Presenilins and Impas: Two Related Families Of Prmentioning

confidence: 99%

The Caenorhabditis elegans IMPAS gene, imp-2, is essential for development and is functionally distinct from related presenilins

Grigorenko

Moliaka

Soto

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

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Lipoprotein receptors and a Disabled family cytoplasmic adaptor protein regulate EGL-17/FGF export in C. elegans

Cited by 43 publications

References 61 publications

Disabled-2 Is an Epithelial Surface Positioning Gene

Disabled-2 Is an Epithelial Surface Positioning Gene

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

The Caenorhabditis elegans IMPAS gene, imp-2, is essential for development and is functionally distinct from related presenilins

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