{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nPITPNM1 (also known as Nir2) plays a central role in nonvesicular lipid signaling and membrane contact site dynamics. It functions at endoplasmic reticulum–plasma membrane junctions to replenish phosphatidylinositol 4,5‐bisphosphate (PIP2) following its receptor‐induced hydrolysis, a process facilitated by calcium‐triggered recruitment of E‑Syt1 and modulation of phosphatidic acid (PA) levels. Moreover, PITPNM1 regulates lipid homeostasis at the Golgi apparatus by maintaining diacylglycerol (DAG) pools critical for proper vesicular trafficking and by coupling PA generation to downstream phosphoinositide signaling via MAPK and PI3K/AKT pathways."}, {"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": "\nIn addition to its roles in lipid transfer, PITPNM1 is pivotal during cell division. It localizes dynamically from the Golgi apparatus to the cleavage furrow and midbody during cytokinesis, a process that is tightly regulated by phosphorylation events. Mitotic kinases such as Cdk1 phosphorylate PITPNM1, thereby facilitating its disengagement from the Golgi and subsequent interaction with cytokinetic effectors including RhoA, a coordination crucial for successful cell division."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nDefects or alterations in PITPNM1 function have significant implications for disease and cellular homeostasis. Specific mutations (for example, T59E) enhance its phosphorylation and aberrant targeting to lipid droplets, providing insights into the mechanisms underlying retinal degeneration observed with its Drosophila homolog. In parallel, PITPNM1 and its RdgB homologs exhibit deoxyribonucleoside triphosphate pyrophosphohydrolase activity to prevent genomic incorporation of noncanonical nucleotides. Furthermore, upregulation of PITPNM1 contributes to epithelial‐mesenchymal transition (EMT) and breast cancer progression via activation of PI3K/AKT and ERK1/2 pathways, and it is co-opted by hepatitis C virus to sustain replication through maintenance of a specialized phosphoinositide environment. Consistently, high expression levels of PITPNM1 correlate with poor patient prognosis in breast cancer."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "7", "end_ref": "11"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Vladimir Litvak, Nili Dahan, Sreekumar Ramachandran, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Maintenance of the diacylglycerol level in the Golgi apparatus by the Nir2 protein is critical for Golgi secretory function."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Cell Biol (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/ncb1221"}], "href": "https://doi.org/10.1038/ncb1221"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15723057"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15723057"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "SoHui Kim, Amir Kedan, Merav Marom, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The phosphatidylinositol-transfer protein Nir2 binds phosphatidic acid and positively regulates phosphoinositide signalling."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "EMBO Rep (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/embor.2013.113"}], "href": "https://doi.org/10.1038/embor.2013.113"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23897088"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23897088"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Chi-Lun Chang, Ting-Sung Hsieh, T Tony Yang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Feedback regulation of receptor-induced Ca2+ signaling mediated by E-Syt1 and Nir2 at endoplasmic reticulum-plasma membrane junctions."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Rep (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.celrep.2013.09.038"}], "href": "https://doi.org/10.1016/j.celrep.2013.09.038"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24183667"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24183667"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Chi-Lun Chang, Jen Liou "}, {"type": "b", "children": [{"type": "t", "text": "Phosphatidylinositol 4,5-Bisphosphate Homeostasis Regulated by Nir2 and Nir3 Proteins at Endoplasmic Reticulum-Plasma Membrane Junctions."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M114.621375"}], "href": "https://doi.org/10.1074/jbc.M114.621375"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25887399"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25887399"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Vladimir Litvak, Donguha Tian, Shari Carmon, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Nir2, a human homolog of Drosophila melanogaster retinal degeneration B protein, is essential for cytokinesis."}]}, {"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.22.14.5064-5075.2002"}], "href": "https://doi.org/10.1128/MCB.22.14.5064-5075.2002"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12077336"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12077336"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Vladimir Litvak, Rachel Argov, Nili Dahan, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Mitotic phosphorylation of the peripheral Golgi protein Nir2 by Cdk1 provides a docking mechanism for Plk1 and affects cytokinesis completion."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Cell (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/s1097-2765(04)00214-x"}], "href": "https://doi.org/10.1016/s1097-2765(04"}, {"type": "t", "text": "00214-x) PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15125835"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15125835"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Vladimir Litvak, Yoav D Shaul, Mark Shulewitz, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Targeting of Nir2 to lipid droplets is regulated by a specific threonine residue within its PI-transfer domain."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Curr Biol (2002)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/s0960-9822(02)01107-7"}], "href": "https://doi.org/10.1016/s0960-9822(02"}, {"type": "t", "text": "01107-7) PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12225667"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12225667"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Nicholas E Burgis, Richard P Cunningham "}, {"type": "b", "children": [{"type": "t", "text": "Substrate specificity of RdgB protein, a deoxyribonucleoside triphosphate pyrophosphohydrolase."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M608708200"}], "href": "https://doi.org/10.1074/jbc.M608708200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17090528"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17090528"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Omer Keinan, Amir Kedan, Nancy Gavert, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The lipid-transfer protein Nir2 enhances epithelial-mesenchymal transition and facilitates breast cancer metastasis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Cell Sci (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1242/jcs.155721"}], "href": "https://doi.org/10.1242/jcs.155721"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25179602"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25179602"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Hongliang Wang, Andrew W Tai "}, {"type": "b", "children": [{"type": "t", "text": "Nir2 Is an Effector of VAPs Necessary for Efficient Hepatitis C Virus Replication and Phosphatidylinositol 4-Phosphate Enrichment at the Viral Replication Organelle."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Virol (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1128/JVI.00742-19"}], "href": "https://doi.org/10.1128/JVI.00742-19"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31484747"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31484747"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Zihao Liu, Yu Shi, Qun Lin, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Attenuation of PITPNM1 Signaling Cascade Can Inhibit Breast Cancer Progression."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biomolecules (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3390/biom11091265"}], "href": "https://doi.org/10.3390/biom11091265"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "34572478"}], "href": "https://pubmed.ncbi.nlm.nih.gov/34572478"}]}]}]}