{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nInositol 1,4,5‐trisphosphate 3-kinase B (Itpkb) is a critical enzyme that phosphorylates IP₃ to generate IP₄, thereby serving as a pivotal regulator of intracellular calcium and phosphoinositide signaling. Structural and biochemical studies have illuminated its mechanisms of autoinhibition and dimerization, and have revealed that, despite the complexity of inositol phosphate metabolism, the production of higher phosphorylated inositol phosphates can occur even in the absence of several Itpk isoenzymes."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn the immune system, Itpkb plays multifaceted roles. In B lymphocytes, it tempers antigen receptor–induced signaling by generating IP₄, which regulates the subcellular localization of Rasa3 and restrains Erk activation, thereby controlling the expression of the proapoptotic Bim protein—a process essential for B cell survival and tolerance. Similarly, within T cells, Itpkb is indispensable for proper thymocyte differentiation and peripheral T cell function; its deficiency leads to hyperresponsive calcium signaling, aberrant activation and metabolic overdrive via unchecked PI3K/Akt/mTOR cascades, and ultimately results in impaired T cell development and survival. In addition, Itpkb is crucial for maintaining hematopoietic stem cell quiescence, as demonstrated by its ability to limit cytokine-induced metabolic activation."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "3", "end_ref": "9"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond lymphoid regulation, Itpkb influences other physiological contexts. Its deficiency prompts enhanced proliferation of granulocyte-monocyte progenitors and increased neutrophil production, highlighting a regulatory role in myelopoiesis. In neuronal cells, Itpkb activity modulates endoplasmic reticulum-to-mitochondria calcium flux; by limiting mitochondrial calcium overload, it acts as a negative regulator of α-synuclein aggregation—implicating it in the pathogenesis of sporadic Parkinson’s disease. Furthermore, in dendritic cells, Itpkb is essential for plasma membrane–associated calcium mobilization and the activation of NFAT transcription factors in response to lipopolysaccharide, contributing to inflammatory responses."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "10", "end_ref": "12"}]}, {"type": "t", "text": ""}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Philip P Chamberlain, Mark L Sandberg, Karsten Sauer, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Structural insights into enzyme regulation for inositol 1,4,5-trisphosphate 3-kinase B."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochemistry (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1021/bi051256q"}], "href": "https://doi.org/10.1021/bi051256q"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16262249"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16262249"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Alexandre Leyman, Valérie Pouillon, Alionka Bostan, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The absence of expression of the three isoenzymes of the inositol 1,4,5-trisphosphate 3-kinase does not prevent the formation of inositol pentakisphosphate and hexakisphosphate in mouse embryonic fibroblasts."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Signal (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.cellsig.2007.01.024"}], "href": "https://doi.org/10.1016/j.cellsig.2007.01.024"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17355905"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17355905"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Yoann Maréchal, Xavier Pesesse, Yonghui Jia, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Inositol 1,3,4,5-tetrakisphosphate controls proapoptotic Bim gene expression and survival in B cells."}]}, {"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.0704312104"}], "href": "https://doi.org/10.1073/pnas.0704312104"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17709751"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17709751"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Andrew T Miller, Daniel R Beisner, Daorong Liu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Inositol 1,4,5-trisphosphate 3-kinase B is a negative regulator of BCR signaling that controls B cell selection and tolerance induction."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Immunol (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.4049/jimmunol.0802850"}], "href": "https://doi.org/10.4049/jimmunol.0802850"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19342645"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19342645"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Yoann Maréchal, Séverine Quéant, Selena Polizzi, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Inositol 1,4,5-trisphosphate 3-kinase B controls survival and prevents anergy in B cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Immunobiology (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.imbio.2010.03.012"}], "href": "https://doi.org/10.1016/j.imbio.2010.03.012"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20452702"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20452702"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Valérie Pouillon, Yoann Maréchal, Christophe Frippiat, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Inositol 1,4,5-trisphosphate 3-kinase B (Itpkb) controls survival, proliferation and cytokine production in mouse peripheral T cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Adv Biol Regul (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.jbior.2012.08.001"}], "href": "https://doi.org/10.1016/j.jbior.2012.08.001"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22981169"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22981169"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Sabine Siegemund, Stephanie Rigaud, Claire Conche, et al. "}, {"type": "b", "children": [{"type": "t", "text": "IP3 3-kinase B controls hematopoietic stem cell homeostasis and prevents lethal hematopoietic failure in mice."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Blood (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1182/blood-2014-06-583187"}], "href": "https://doi.org/10.1182/blood-2014-06-583187"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25788703"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25788703"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Andrew T Miller, Carol Dahlberg, Mark L Sandberg, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Inhibition of the Inositol Kinase Itpkb Augments Calcium Signaling in Lymphocytes and Reveals a Novel Strategy to Treat Autoimmune Disease."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS One (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pone.0131071"}], "href": "https://doi.org/10.1371/journal.pone.0131071"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26121493"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26121493"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Luise Westernberg, Claire Conche, Yina Hsing Huang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Non-canonical antagonism of PI3K by the kinase Itpkb delays thymocyte β-selection and renders it Notch-dependent."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Elife (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.7554/eLife.10786"}], "href": "https://doi.org/10.7554/eLife.10786"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26880557"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26880557"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Yonghui Jia, Fabien Loison, Hidenori Hattori, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Inositol trisphosphate 3-kinase B (InsP3KB) as a physiological modulator of myelopoiesis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Proc Natl Acad Sci U S A (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1073/pnas.0800218105"}], "href": "https://doi.org/10.1073/pnas.0800218105"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18339802"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18339802"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Daniel J Apicco, Evgeny Shlevkov, Catherine L Nezich, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The Parkinson's disease-associated gene ITPKB protects against α-synuclein aggregation by regulating ER-to-mitochondria calcium release."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Proc Natl Acad Sci U S A (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1073/pnas.2006476118"}], "href": "https://doi.org/10.1073/pnas.2006476118"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "33443159"}], "href": "https://pubmed.ncbi.nlm.nih.gov/33443159"}]}, {"type": "r", "ref": 12, "children": [{"type": "t", "text": "Laura Marongiu, Francesca Mingozzi, Clara Cigni, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Inositol 1,4,5-trisphosphate 3-kinase B promotes Ca"}, {"type": "a", "children": [{"type": "t", "text": "sup"}], "href": "sup"}, {"type": "t", "text": "2+"}, {"type": "a", "children": [{"type": "t", "text": "/sup"}], "href": "/sup"}, {"type": "t", "text": " mobilization and the inflammatory activity of dendritic cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Sci Signal (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1126/scisignal.aaz2120"}], "href": "https://doi.org/10.1126/scisignal.aaz2120"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "33785611"}], "href": "https://pubmed.ncbi.nlm.nih.gov/33785611"}]}]}]}