{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nULK2 is a serine/threonine kinase that plays a central role in initiating autophagy. It functions as part of the ULK–ATG13–FIP200 complex whose assembly and activity are finely regulated by upstream signals such as mTOR. In response to nutrient deprivation and DNA damage, ULK2 expression is up‐regulated—being a direct transcriptional target of p53—to sustain autophagic activity, and its kinase activity is further modulated by direct binding of copper, which enhances its function. These findings were originally identified in broad kinome cataloguing studies and have established ULK2 as a key autophagy regulator."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "4"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond initiating autophagy, ULK2 plays multifaceted roles in cellular stress responses, metabolic reprogramming, and tumor suppression. In diverse cancer models such as glioblastoma, prostate, laryngeal, and diffuse‐type gastric cancers, ULK2 expression is often down‐regulated through promoter hypermethylation or microRNA targeting, leading to impaired autophagy induction, enhanced epithelial–mesenchymal transition, and altered cell survival. Moreover, ULK2 phosphorylates substrates that regulate autophagosome trafficking (via DENND3/Rab12), reprograms glucose metabolism by modifying key glycolytic enzymes, and in keratinocytes it modulates NF‐κB signaling through phosphorylation of CARMA2sh. Such activities have been linked to both reduced tumor growth and chemoresistance, as evidenced by studies in lung and acute myeloid leukemia models. In addition, genetic studies have implicated ULK2 polymorphisms in psychiatric conditions such as schizophrenia, and its role in mechanotransduction via paxillin phosphorylation further underscores its influence on cell adhesion and migration."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "5", "end_ref": "17"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nStructural and regulatory studies have further refined our understanding of ULK2. Its subcellular localization is controlled by a PY–nuclear localization signal that mediates its interaction with karyopherin β2 and is influenced by phosphorylation events such as those catalyzed by protein kinase A. High‐resolution structural analyses have revealed that ULK2 can form dimeric assemblies reminiscent of autoactivating kinases, providing insight into its activation mechanism. Interestingly, ULK2 may be bypassed or inactivated during viral infections (e.g. by cleavage via viral proteinases), and its activity is also negatively regulated by PKCλ/ι via phosphorylation that impacts interferon signaling. In addition, noncoding RNAs—including specific microRNAs and circular RNAs—modulate ULK2 expression to affect autophagy-related outcomes in contexts such as diabetic wound healing. Notably, while genome-wide surveys have catalogued ULK2 among the human kinome, studies in other conditions like primary open angle glaucoma did not reveal a direct role for ULK2, underscoring the importance of context in its function."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "18", "end_ref": "24"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "G Manning, D B Whyte, R Martinez, et al. 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