{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n DLK2 is a transmembrane protein containing epidermal growth factor–like repeats that is highly homologous to DLK1. In several mammalian contexts, DLK2 functions as a non‐canonical inhibitor of Notch signaling by binding to the Notch1 receptor – either as a homodimer or in heteromeric complexes with DLK1 – thereby modulating key cellular processes such as differentiation and proliferation (1,6,7). In adipogenic models, DLK2 is part of a coordinated regulatory network with DLK1; its expression is inversely correlated with that of DLK1, and its modulation can either promote or inhibit adipocyte differentiation depending on the cellular context and transcriptional regulation by factors such as KLF4 (2,3). In chondrogenesis, overexpression of DLK2 in ATDC5 cells has been shown to enhance cell growth while simultaneously inhibiting insulin‐induced differentiation through activation of the p38 MAP kinase pathway, with silencing of DLK2 producing the converse effects, thereby underscoring its role as a fine regulator of cartilage formation (4). During embryonic development, the broad and often overlapping distribution of DLK2 alongside DLK1 in tissues derived from all three germ layers suggests that these proteins may act synergistically to influence cell fate decisions (5)."}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n In cancer, DLK2’s ability to attenuate Notch signaling appears to be dose dependent. For example, in breast cancer models, low levels of DLK2 expression have been associated with moderate Notch inhibition and enhanced cell proliferation and invasion, while higher levels lead to marked Notch suppression, reduced proliferation, and promotion of apoptosis. Similar dose-dependent effects on tumor cell behavior have also been described in metastatic melanoma cells (6,7). In clear cell renal cell carcinoma, elevated expression of DLK2 correlates with advanced tumor stage, extracellular matrix remodeling, and poor patient prognosis, indicating that DLK2 may contribute to tumor progression by impacting cell metabolism and signaling pathways including Notch (10)."}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Beyond its roles in modulating cell differentiation and tumorigenesis, DLK2 expression is dynamically regulated during tissue injury and repair. Upregulation of DLK2 has been observed in kidney injury models where, in the absence of DLK1, increased DLK2 expression is linked with enhanced Notch activity and a concomitant pro‐inflammatory Th17 response (8). Moreover, in non‐mammalian systems DLK2 homologs also participate in critical developmental processes. For instance, the tomato protein SlDLK2 is expressed in roots in an arbuscular mycorrhizal–dependent manner, where its overexpression arrests arbuscule branching and downregulates symbiosis-responsive genes through interaction with the DELLA regulatory protein (9)."}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n In addition to its roles in cell differentiation, metabolism, and cancer, genetic studies have associated DLK2 with organismal traits. Polymorphisms in the DLK2 gene correlate with growth and meat quality traits in cattle (11), and DLK2 has also been identified among a set of neurodevelopmental genes implicated in suicidal behavior (12). Finally, DLK2 is induced as part of a karrikin/strigolactone signaling cascade in plants, where its expression serves as a transcriptional marker of the pathway (13). Collectively, these studies reveal that DLK2 is a versatile modulator of Notch signaling and a key regulator of diverse biological processes including embryonic development, adipogenesis, chondrogenesis, inflammatory responses, and oncogenesis."}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "13"}]}, {"type": "t", "text": ""}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Beatriz Sánchez-Solana, María Luisa Nueda, María Desamparados Ruvira, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The EGF-like proteins DLK1 and DLK2 function as inhibitory non-canonical ligands of NOTCH1 receptor that modulate each other's activities."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochim Biophys Acta (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.bbamcr.2011.03.004"}], "href": "https://doi.org/10.1016/j.bbamcr.2011.03.004"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21419176"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21419176"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "María-Luisa Nueda, Victoriano Baladrón, José-Javier García-Ramírez, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The novel gene EGFL9/Dlk2, highly homologous to Dlk1, functions as a modulator of adipogenesis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Mol Biol (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.jmb.2006.10.020"}], "href": "https://doi.org/10.1016/j.jmb.2006.10.020"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17320102"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17320102"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Samuel Rivero, María J M Díaz-Guerra, Eva M Monsalve, et al. 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