{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n Dickkopf‐2 (DKK2) is emerging as a context‐dependent modulator of Wnt signaling that can function either as an antagonist or, under specific molecular conditions, as an activator of the canonical Wnt/β–catenin pathway. In early developmental systems, studies in Xenopus demonstrate that while DKK proteins classically inhibit Wnt8 signaling through binding to LRP6, DKK2 in particular can activate canonical Wnt signaling upon interacting with the Wnt coreceptor LRP6, thereby illustrating that its effects depend on molecular context."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " \n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n In the developing eye, DKK2 is expressed in specific progenitor populations where its activity is essential for proper cell‐fate specification. By repressing canonical Wnt signaling, DKK2 ensures the differentiation of corneal epithelial progenitor cells into a non‐keratinizing stratified epithelium, thereby preventing aberrant acquisition of epidermal traits and the emergence of ectopic blood vessels."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": " \n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n In oncogenesis the role of DKK2 appears as a tumor‐suppressive barrier against excessive Wnt activation. In renal cell carcinoma, for instance, DKK2 is both targeted for epigenetic silencing and directly repressed by oncogenic microRNAs – such as miR‐1260b – which leads to enhanced Wnt/β–catenin signaling and increased cellular proliferation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": " Similarly, in oral tongue squamous cell carcinoma, miR‐21–mediated downregulation of DKK2 correlates with increased invasiveness via deregulation of the Wnt pathway."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": " \n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n During odontogenesis, BMP4‐regulated expression of Wnt inhibitors within the dental mesenchyme includes DKK2, which is found at higher levels in mandibular molar mesenchyme compared with maxillary regions. Upregulation of DKK2 in this context has been associated with the arrest of tooth development, suggesting that precise regulation of DKK2 expression is critical for proper tooth morphogenesis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": " \n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n In vascular biology, endothelial studies reveal that DKK2 plays a stimulatory role in angiogenesis. DKK2 promotes filopodial dynamics and sprouting of endothelial cells via an LRP6‐mediated activation cascade that involves APC, Asef2, and Cdc42. This angiogenic promotion contrasts with the inhibitory effects of its homolog DKK1, delineating distinct roles within the Dickkopf family."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": " \n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n In the skeleton, DKK2 is implicated as a negative regulator of osteogenesis. Studies in human adipose‐derived stem cells and in bone marrow stromal cells indicate that targeting of DKK2 by microRNAs (e.g., miR‐218) or its down‐regulation by mechanical stress and FGF2 signaling results in enhanced canonical Wnt signaling that favors osteoblastic differentiation and bone formation. Conversely, maintenance of DKK2 expression normally exerts a restraining effect on bone formation."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "8", "end_ref": "10"}]}, {"type": "t", "text": " \n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Collectively, these findings support the view that DKK2 is a versatile regulator of Wnt signaling whose function is highly dependent on cell type and context. It can act to antagonize Wnt-mediated effects in the eye, tooth, and tumor environments, while in endothelial cells it serves to promote angiogenesis. In bone, its downregulation under osteogenic stimuli relieves inhibitory signaling to facilitate bone formation. This dynamic regulation highlights DKK2 as a promising target for therapeutic intervention in developmental anomalies, cancer, and regenerative medicine.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Barbara K Brott, Sergei Y Sokol "}, {"type": "b", "children": [{"type": "t", "text": "Regulation of Wnt/LRP signaling by distinct domains of Dickkopf proteins."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Cell Biol (2002)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1128/MCB.22.17.6100-6110.2002"}], "href": "https://doi.org/10.1128/MCB.22.17.6100-6110.2002"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12167704"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12167704"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Mahua Mukhopadhyay, Marat Gorivodsky, Svetlana Shtrom, et al. 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