Calcium Depletion Dissociates and Activates Heterodimeric Notch Receptors

Rand, Matthew D.; Grimm, Lisa; Artavanis‐Tsakonas, Spyros; Patriub, Vytas; Blacklow, Stephen C.; Sklar, Jeffrey; Aster, Jon C.

doi:10.1128/mcb.20.5.1825-1835.2000

Cited by 375 publications

(345 citation statements)

References 49 publications

(87 reference statements)

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“…33 Bozkulak and Weinmaster also saw that when EDTA, which has been shown to cause dissociation of the Notch heterodimer (destabilizing the NRR), was added to cells expressing wild-type Notch, the constitutively active Notch readout was defective only when ADAM17 was depleted. 14, 35 These data indicate that ADAM10 is not important for Notch cleavage during ligand-independent NRR destabilization and that ADAM17 is the major S2 protease in this case. The findings discussed above are summarized in Figure 1.…”

Section: Do Not Distributementioning

confidence: 83%

The ADAM family

Christian

2012

Fly

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Section: Do Not Distributementioning

confidence: 83%

The ADAM family

Christian

2012

Fly

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“…3A) nor did lysis in radioimmune precipitation assay buffer containing 0.1% SDS (w/v) and warming (supplemental Fig. S3 and data not shown), conditions that have been reported to be sufficient to disrupt the Notch heterodimer (27). However, increasing the concentration of SDS in the cell lysis to 1% showed that the p430 and p85 bands could be individually precipitated by the NTD and CTD mAbs, respectively, indicating the dissociation of the FAT1 heterodimer (supplemental Fig.…”

Section: Fat1 Is Proteolytically Processed Before Achieving Cell Surfmentioning

confidence: 99%

Dual Processing of FAT1 Cadherin Protein by Human Melanoma Cells Generates Distinct Protein Products

Sadeqzadeh

Bock

Zhang

et al. 2011

Journal of Biological Chemistry

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The giant cadherin FAT1 is one of four vertebrate orthologues of the Drosophila tumor suppressor fat. It engages in several functions, including cell polarity and migration, and in Hippo signaling during development. Homozygous deletions in oral cancer suggest that FAT1 may play a tumor suppressor role, although overexpression of FAT1 has been reported in some other cancers. Here we show using Northern blotting that human melanoma cell lines variably but universally express FAT1 and less commonly FAT2, FAT3, and FAT4. Both normal melanocytes and keratinocytes also express comparable FAT1 mRNA relative to melanoma cells. Analysis of the protein processing of FAT1 in keratinocytes revealed that, like Drosophila FAT, human FAT1 is cleaved into a non-covalent heterodimer before achieving cell surface expression. The use of inhibitors also established that such cleavage requires the proprotein convertase furin. However, in melanoma cells, the non-cleaved proform of FAT1 is also expressed at the cell surface together with the furin-cleaved heterodimer. Moreover, furin-independent processing generates a potentially functional proteolytic product in melanoma cells, a persistent 65-kDa membrane-bound cytoplasmic fragment no longer in association with the extracellular fragment. In vitro localization studies of FAT1 showed that melanoma cells display high levels of cytosolic FAT1 protein, whereas keratinocytes, despite comparable FAT1 expression levels, exhibited mainly cell-cell junctional staining. Such differences in protein distribution appear to reconcile with the different protein products generated by dual FAT1 processing. We suggest that the uncleaved FAT1 could promote altered signaling, and the novel products of alternate processing provide a dominant negative function in melanoma.

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“…Haritunians et al (2002) found that a mutant Notch3 receptor (93% and 84% homologous to murine and human Notch3 respectively) expressed in a human cell line, has normal cell maturation and expression and also normal binding capacity. The author, therefore, suggests that CADASIL mutations act downstream of ligand binding, probably altering Notch3ECD clearance induced by the ligand, a process important for receptor activation (Rand et al, 2000).…”

Section: Do Cadasil Mutations Lead To Loss Of Receptor Function or Acmentioning

confidence: 99%

Physiology and pathology of notch signalling system

Bianchi

Dotti

Federico

2005

Journal Cellular Physiology

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Notch proteins encode a family of transmembrane receptors that are part of a signalling transduction system known as Notch signalling, an extremely conserved and widely used mechanism regulating programs governing growth, apoptosis and differentiation in metazoans. Notch signalling begins when the Notch receptor binds ligands and ends when the Notch intracellular domain enters the nucleus and activates transcription of target genes. This core pathway is subjected to a wide array of regulatory influences and protein-protein interactions and is correlated with other signalling pathway. This review will sumarize recent findings concerning the physiology and pathology of Notch signalling in vascular development and homeostasis. Moreover, the clinical phenotypes of Notch3 signalling system pathology will be described, with particular regard to CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy) for which the most recent pathogenetic hypotheses are reported.

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Calcium Depletion Dissociates and Activates Heterodimeric Notch Receptors

Cited by 375 publications

References 49 publications

The ADAM family

The ADAM family

Dual Processing of FAT1 Cadherin Protein by Human Melanoma Cells Generates Distinct Protein Products

Physiology and pathology of notch signalling system

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