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General Comment |
Evidence of non-canonical NOTCH signaling: Delta-like 1 homolog (DLK1) directly interacts with the NOTCH1 receptor in mammals. Traustadóttir GÁ et al. (2016) Canonical NOTCH signaling, known to be essential for tissue development, requires the Delta-Serrate-LAG2 (DSL) domain for NOTCH to interact with its ligand. However, despite lacking DSL, Delta-like 1 homolog (DLK1), a protein that plays a significant role in mammalian development, has been suggested to interact with NOTCH1 and act as an antagonist. This non-canonical interaction is, however controversial, and evidence for a direct interaction, still lacking in mammals. In this study, we elucidated the putative DLK1-NOTCH1 interaction in a mammalian context. Taking a global approach and using Dlk1(+/+) and Dlk1(-/-) mouse tissues at E16.5, we demonstrated that several NOTCH signaling pathways indeed are affected by DLK1 during tissue development, and this was supported by a lower activation of NOTCH1 protein in Dlk1(+/+) embryos. Likewise, but using a distinct Dlk1-manipulated (siRNA) setup in a mammalian cell line, NOTCH signaling was substantially inhibited by DLK1. Using a mammalian two-hybrid system, we firmly established that the effect of DLK1 on NOTCH signaling was due to a direct interaction between DLK1 and NOTCH1. By careful dissection of this mechanism, we found this interaction to occur between EGF domains 5 and 6 of DLK1 and EGF domains 10-15 of NOTCH1. Thus, our data provide the first evidence for a direct interaction between DLK1 and NOTCH1 in mammals, and substantiate that non-canonical NOTCH ligands exist, adding to the complexity of NOTCH signaling.//////////////////
Laborda et al. (1993) isolated human and mouse cDNAs encoding a protein that they designated DLK (Delta-like) because of its homology to the Drosophila neurogenic protein Delta, which is involved in neural differentiation. The predicted 383-amino acid human protein shares 86% identity with mouse Dlk. Both human and mouse DLK contain 6 EGF-like repeats, a transmembrane region, and a signal peptide domain. Northern blot analysis revealed that the DLK gene was expressed in tumors with neuroendocrine features, such as neuroblastoma, pheochromocytoma, and a subset of small cell lung carcinoma cell lines; however, its expression in normal tissues was restricted to the adrenal gland and placenta. The authors suggested that DLK may be involved in neuroendocrine differentiation.
NCBI Summary:
This gene encodes a transmembrane protein that contains multiple epidermal growth factor repeats that functions as a regulator of cell growth. The encoded protein is involved in the differentiation of several cell types including adipocytes. This gene is located in a region of chromosome 14 frequently showing unparental disomy, and is imprinted and expressed from the paternal allele. A single nucleotide variant in this gene is associated with child and adolescent obesity and shows polar overdominance, where heterozygotes carrying an active paternal allele express the phenotype, while mutant homozygotes are normal. [provided by RefSeq, Nov 2015]
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Comment |
Hedlund GP, et al reported that Fetal antigen 1 (FA1) in the adult rat adrenal gland, ovary and pituitary gland.
Fetal antigen 1 (FA1) is a circulating glycoprotein containing six epidermal growth factor
(EGF)-like repeats. FA1's larger membrane-bound precursor is defined by the cDNAs referred to as
either human delta-like (dlk) or human adrenal specific cDNA, pG2. In rodents FA1 has also been
studied under the names of preadipocyte factor 1 (Pref-1), and zona glomerulosa-specific factor
(ZOG). FA1 is abundantly expressed in fetal tissues, but in the mature cells of the adult organism the
tissue presence of the protein seems to be restricted to neuroendocrine tissues. The present study
demonstrates FA1 localisation in endocrine tissues of the adult female rat in which the protein was
found present in the medulla and the zona glomerulosa of the cortex of the adrenal glands, in the pars
distalis of the adenohypophysis, and in the ovarian granulosa lutein cells. No staining was found in
the pancreas, which is in contrast to what has been described in the human.
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