{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nSalt‑inducible kinase 1 (SIK1) is a multifunctional serine/threonine kinase that modulates transcriptional responses by acting downstream of cAMP signaling. It regulates the activity of the cAMP response element‑binding protein (CREB) and its coactivators, with its activity tightly controlled by protein kinase A–dependent phosphorylation events that promote binding to 14‑3‑3 proteins, thereby tuning substrate specificity and signaling output."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn epithelial cells, SIK1 is activated in response to elevations in intracellular sodium and calcium. Once activated, it associates with the Na⁺,K⁺‑ATPase regulatory complex to promote dephosphorylation of the α‑subunit, thereby enhancing ion pump activity and fluid clearance. In parallel, SIK1 is induced by transforming growth factor‑β (TGF‑β)/Smad signaling and forms complexes with inhibitory Smad7 to facilitate degradation of the activated type I receptor, effectively tempering TGF‑β pathway activity."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "3", "end_ref": "5"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nSIK1 also plays a pivotal tumor‑suppressive role. By linking the upstream tumor suppressor LKB1 to p53‑dependent anoikis, SIK1 promotes cell death upon loss of adhesion, thereby preventing anchorage‑independent growth and metastasis. This axis not only constrains malignant transformation but also reinforces cellular quality control during tissue homeostasis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn hormone‑responsive and hepatic cells, extracellular cues such as gastrin and sustained cAMP signaling induce SIK1 expression. Once expressed, SIK1 phosphorylates class II histone deacetylases (e.g., HDAC4) and modulates the stability of CREB‑regulated transcription coactivators (CRTC1 and CRTC2), thereby suppressing the expression of gluconeogenic genes. This regulation occurs via SIK1‑induced ubiquitination and proteasomal degradation of these coactivators, integrating metabolic signals with gene expression programs."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "8", "end_ref": "10"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its roles in metabolism and tumor suppression, SIK1 is crucial for proper neurodevelopment and inflammatory regulation. Mutations in SIK1 have been linked to severe developmental epilepsies that are characterized by disrupted MEF2C signaling and aberrant neuronal morphology. Moreover, modulation of SIK1 activity in immune cells influences macrophage polarization by limiting proinflammatory cytokine production while favoring anti‑inflammatory responses; similar regulatory mechanisms may also impact epithelial‑to‑mesenchymal transition during the progression from acute kidney injury to chronic kidney disease."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "11", "end_ref": "14"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn a cancer context, downregulation or degradation of SIK1 is associated with enhanced tumor aggressiveness. In ovarian cancer, loss of SIK1 correlates with increased stem‑like properties and a shift toward a more invasive, epithelial‑to‑mesenchymal phenotype—partly through mechanisms involving NaV1.5 channel regulation. In hepatocellular carcinoma, targeting of SIK1 by the ubiquitin ligase RNF2 contributes to malignancy, while its influence on DNA replication through the phosphorylation of MCM2 underscores a broader role in cell cycle control. Altered expression of SIK1 and related noncoding RNAs is also evident in non‑small‑cell lung cancer and in comorbid conditions linking type 2 diabetes with breast cancer, highlighting its emerging role as a biomarker in diverse malignancies."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "15", "end_ref": "19"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nCollectively, the diverse cellular functions of SIK1—from modulating transcription and ion transport to enforcing tumor suppression, regulating metabolism, and guiding neural as well as immune homeostasis—underscore its status as a pleiotropic regulator. The central integrative role of SIK1 in these varied signaling networks makes it an attractive candidate for biomarker development and therapeutic intervention in cancer, metabolic disorders, neurodevelopmental diseases, and inflammation‐associated pathologies."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "20"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Hiroshi Takemori, Junko Kajimura, Mitsuhiro Okamoto "}, {"type": "b", "children": [{"type": "t", "text": "TORC-SIK cascade regulates CREB activity through the basic leucine zipper domain."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "FEBS J (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/j.1742-4658.2007.05889.x"}], "href": "https://doi.org/10.1111/j.1742-4658.2007.05889.x"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17565599"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17565599"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Tim Sonntag, Joan M Vaughan, Marc Montminy "}, {"type": "b", "children": [{"type": "t", "text": "14-3-3 proteins mediate inhibitory effects of cAMP on salt-inducible kinases (SIKs)."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "FEBS J (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/febs.14351"}], "href": "https://doi.org/10.1111/febs.14351"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "29211348"}], "href": "https://pubmed.ncbi.nlm.nih.gov/29211348"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Mattias Sjöström, Karin Stenström, Kristina Eneling, et al. "}, {"type": "b", "children": [{"type": "t", "text": "SIK1 is part of a cell sodium-sensing network that regulates active sodium transport through a calcium-dependent process."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Proc Natl Acad Sci U S A (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1073/pnas.0706838104"}], "href": "https://doi.org/10.1073/pnas.0706838104"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17939993"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17939993"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Marcin Kowanetz, Peter Lönn, Michael Vanlandewijck, et al. "}, {"type": "b", "children": [{"type": "t", "text": "TGFbeta induces SIK to negatively regulate type I receptor kinase signaling."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Cell Biol (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1083/jcb.200804107"}], "href": "https://doi.org/10.1083/jcb.200804107"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18725536"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18725536"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Kristina Eneling, Jiwang Chen, Lynn C Welch, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Salt-inducible kinase 1 is present in lung alveolar epithelial cells and regulates active sodium transport."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochem Biophys Res Commun (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.bbrc.2011.04.100"}], "href": "https://doi.org/10.1016/j.bbrc.2011.04.100"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21549091"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21549091"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Hailing Cheng, Pixu Liu, Zhigang C Wang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "SIK1 couples LKB1 to p53-dependent anoikis and suppresses metastasis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Sci Signal (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1126/scisignal.2000369"}], "href": "https://doi.org/10.1126/scisignal.2000369"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19622832"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19622832"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Christopher W Murray, Jennifer J Brady, Min K Tsai, et al. "}, {"type": "b", "children": [{"type": "t", "text": "An LKB1-SIK Axis Suppresses Lung Tumor Growth and Controls Differentiation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer Discov (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1158/2159-8290.CD-18-1237"}], "href": "https://doi.org/10.1158/2159-8290.CD-18-1237"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31350327"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31350327"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Linn-Karina M Selvik, Shalini Rao, Tonje S Steigedal, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Salt-inducible kinase 1 (SIK1) is induced by gastrin and inhibits migration of gastric adenocarcinoma cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS One (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pone.0112485"}], "href": "https://doi.org/10.1371/journal.pone.0112485"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25384047"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25384047"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Wei-Wei Gao, Hei-Man Vincent Tang, Yun Cheng, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Suppression of gluconeogenic gene transcription by SIK1-induced ubiquitination and degradation of CRTC1."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochim Biophys Acta Gene Regul Mech (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.bbagrm.2018.01.021"}], "href": "https://doi.org/10.1016/j.bbagrm.2018.01.021"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "29408765"}], "href": "https://pubmed.ncbi.nlm.nih.gov/29408765"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Chang Wang, Daofei Song, Jiahui Fu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "SIK1 Regulates CRTC2-Mediated Gluconeogenesis Signaling Pathway in Human and Mouse Liver Cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Front Endocrinol (Lausanne) (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3389/fendo.2020.00580"}], "href": "https://doi.org/10.3389/fendo.2020.00580"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "33013689"}], "href": "https://pubmed.ncbi.nlm.nih.gov/33013689"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Jeanne Hansen, Chelsi Snow, Emily Tuttle, et al. "}, {"type": "b", "children": [{"type": "t", "text": "De novo mutations in SIK1 cause a spectrum of developmental epilepsies."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Hum Genet (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.ajhg.2015.02.013"}], "href": "https://doi.org/10.1016/j.ajhg.2015.02.013"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25839329"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25839329"}]}, {"type": "r", "ref": 12, "children": [{"type": "t", "text": "Maria Stella Lombardi, Corine Gilliéron, Damien Dietrich, et al. "}, {"type": "b", "children": [{"type": "t", "text": "SIK inhibition in human myeloid cells modulates TLR and IL-1R signaling and induces an anti-inflammatory phenotype."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Leukoc Biol (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1189/jlb.2A0715-307R"}], "href": "https://doi.org/10.1189/jlb.2A0715-307R"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26590148"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26590148"}]}, {"type": "r", "ref": 13, "children": [{"type": "t", "text": "Christoph Pröschel, Jeanne N Hansen, Adil Ali, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Epilepsy-causing sequence variations in SIK1 disrupt synaptic activity response gene expression and affect neuronal morphology."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Eur J Hum Genet (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/ejhg.2016.145"}], "href": "https://doi.org/10.1038/ejhg.2016.145"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27966542"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27966542"}]}, {"type": "r", "ref": 14, "children": [{"type": "t", "text": "Jinxiu Hu, Jiao Qiao, Qun Yu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Role of SIK1 in the transition of acute kidney injury into chronic kidney disease."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Transl Med (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1186/s12967-021-02717-5"}], "href": "https://doi.org/10.1186/s12967-021-02717-5"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "33588892"}], "href": "https://pubmed.ncbi.nlm.nih.gov/33588892"}]}, {"type": "r", "ref": 15, "children": [{"type": "t", "text": "Jin-Long Chen, Fang Chen, Ting-Ting Zhang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Suppression of SIK1 by miR-141 in human ovarian cancer cell lines and tissues."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Int J Mol Med (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3892/ijmm.2016.2553"}], "href": "https://doi.org/10.3892/ijmm.2016.2553"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27081781"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27081781"}]}, {"type": "r", "ref": 16, "children": [{"type": "t", "text": "Kiranmai Joshi, Varun Jayeshkumar Shah, Subbareddy Maddika "}, {"type": "b", "children": [{"type": "t", "text": "GINS complex protein Sld5 recruits SIK1 to activate MCM helicase during DNA replication."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Signal (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.cellsig.2016.08.018"}], "href": "https://doi.org/10.1016/j.cellsig.2016.08.018"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27592030"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27592030"}]}, {"type": "r", "ref": 17, "children": [{"type": "t", "text": "Chao Qu, Yaqin Qu "}, {"type": "b", "children": [{"type": "t", "text": "Down-regulation of salt-inducible kinase 1 (SIK1) is mediated by RNF2 in hepatocarcinogenesis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Oncotarget (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.18632/oncotarget.13673"}], "href": "https://doi.org/10.18632/oncotarget.13673"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27911266"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27911266"}]}, {"type": "r", "ref": 18, "children": [{"type": "t", "text": "Alireza Anvarnia, Reza Panahizadeh, Habib Zarredar, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Down-regulation and Clinic-pathological Correlation of SIK-1 and SIK-1-LNC in Non-small Cell Lung Cancer Patients"}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Asian Pac J Cancer Prev (2023)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.31557/APJCP.2023.24.4.1407"}], "href": "https://doi.org/10.31557/APJCP.2023.24.4.1407"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "37116165"}], "href": "https://pubmed.ncbi.nlm.nih.gov/37116165"}]}, {"type": "r", "ref": 19, "children": [{"type": "t", "text": "Ilhaam Ayaz Durrani, Attya Bhatti, Peter John "}, {"type": "b", "children": [{"type": "t", "text": "Integrated bioinformatics analyses identifying potential biomarkers for type 2 diabetes mellitus and breast cancer: In SIK1-ness and health."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS One (2023)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pone.0289839"}], "href": "https://doi.org/10.1371/journal.pone.0289839"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "37556419"}], "href": "https://pubmed.ncbi.nlm.nih.gov/37556419"}]}, {"type": "r", "ref": 20, "children": [{"type": "t", "text": "Xinran Zhang, Jing Liu, Chenyang Zuo, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Role of SIK1 in tumors: Emerging players and therapeutic potentials (Review)."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Oncol Rep (2024)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3892/or.2024.8828"}], "href": "https://doi.org/10.3892/or.2024.8828"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "39422046"}], "href": "https://pubmed.ncbi.nlm.nih.gov/39422046"}]}]}]}