{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nSTK33 is a serine/threonine kinase with a tightly regulated, tissue‐specific expression pattern. In non‐neoplastic tissues, it is expressed at relatively low levels in most organs but shows particularly high expression in the testis, where studies suggest it may play a role in spermatogenesis and reproductive organ development. Moreover, genetic investigations have associated variants in the STK33 locus with alterations in body mass, while a deleterious frameshift mutation has been linked to male infertility characterized by severe defects in sperm flagellar formation."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "3"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn the context of cancer, STK33 appears to function as a pro-tumorigenic effector in multiple malignancies. Although early results suggested that STK33 might be essential for the survival of mutant KRAS‐dependent tumors, later investigations refuted this connection, indicating that its oncogenic potential is cancer type–dependent. Elevated expression of STK33 has been documented in pancreatic ductal adenocarcinoma, gastric cancer, lung cancer, hepatocellular carcinoma, and hypopharyngeal squamous cell carcinoma, where it promotes proliferation, migration, invasion, and the epithelial–mesenchymal transition. In small cell lung cancer, for example, STK33 depletion induces apoptosis via the mitochondrial pathway, while in other cancers its expression is found to be under the transcriptional control of factors such as hypoxia-inducible factor 1α and Krüppel-like factor 4."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "4", "end_ref": "12"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nMechanistically, STK33 modulates key oncogenic and survival signaling pathways. It can act as an upstream kinase that phosphorylates substrates such as extracellular signal–regulated kinase 2 (ERK2), thereby enhancing proliferative signaling, and it influences apoptotic mediators including RPS6 and BAD. This regulation appears to be context-specific, with distinct transcriptional regulators controlling its expression in different tumor types. Emerging evidence also suggests a role for STK33 in renal cell carcinoma via the modulation of autophagy, further underscoring its potential as a therapeutic target across a broad spectrum of neoplastic and non‐neoplastic conditions."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "12"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Alejandro O Mujica, Bastienne Brauksiepe, Sigrid Saaler-Reinhardt, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "The STK33-linked SNP rs4929949 is associated with obesity and BMI in two independent cohorts of Swedish and Greek children."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS One (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pone.0071353"}], "href": "https://doi.org/10.1371/journal.pone.0071353"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23967198"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23967198"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Hui Ma, Beibei Zhang, Asad Khan, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Novel frameshift mutation in STK33 is associated with asthenozoospermia and multiple morphological abnormalities of the flagella."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Hum Mol Genet (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/hmg/ddab165"}], "href": "https://doi.org/10.1093/hmg/ddab165"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "34155512"}], "href": "https://pubmed.ncbi.nlm.nih.gov/34155512"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Carol Babij, Yihong Zhang, Robert J Kurzeja, et al. 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