{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n EXTL2 is a multifunctional member of the exostosin gene family that encodes an α1,4–N‐acetylhexosaminyltransferase critically involved in glycosaminoglycan (GAG) and heparan sulfate (HS) biosynthesis. Structural and biochemical studies have shown that EXTL2 transfers N‐acetylglucosamine (GlcNAc) from UDP–GlcNAc—and, to a lesser degree, N‐acetylgalactosamine (GalNAc) from UDP–GalNAc—to acceptor substrates that mimic the common GAG–protein linkage region. Its active site contains highly conserved residues that ensure proper donor binding and catalytic efficiency, thereby playing a key role in the initiation of HS synthesis."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "4"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n In addition to initiating HS chain synthesis, EXTL2 plays a regulatory “quality control” role by transferring a GlcNAc residue to the phosphorylated tetrasaccharide linkage region. This action terminates chain elongation by the HS and chondroitin sulfate polymerases, thereby controlling the overall production and structure of GAGs. Accordingly, loss or knockdown of EXTL2 leads to increased GAG synthesis with enhanced HS chain lengths, alterations in fibroblast growth factor 2 (FGF2) signaling, and downstream effects on tissue regeneration and pathological processes such as impaired liver repair and vascular calcification."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "5", "end_ref": "7"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Functional studies employing RNA interference further underscore the critical role of EXTL2 in modulating HS biosynthesis and cellular signaling pathways. Targeted silencing of EXTL2 alters GAG synthesis, thereby affecting cellular responses and signaling cascades."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n In summary, EXTL2 functions both as an initiator of heparan sulfate synthesis and as a chain-terminating regulator, ensuring proper control over GAG chain length and structure. Through these dual roles, it helps maintain appropriate extracellular matrix composition and modulates growth factor–mediated signaling events that are essential for tissue homeostasis and repair.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Lars C Pedersen, Jian Dong, Fumiyasu Taniguchi, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Crystal structure of an alpha 1,4-N-acetylhexosaminyltransferase (EXTL2), a member of the exostosin gene family involved in heparan sulfate biosynthesis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M210532200"}], "href": "https://doi.org/10.1074/jbc.M210532200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12562774"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12562774"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Mack Sobhany, Jian Dong, Masahiko Negishi "}, {"type": "b", "children": [{"type": "t", "text": "Two-step mechanism that determines the donor binding specificity of human UDP-N-acetylhexosaminyltransferase."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M413379200"}], "href": "https://doi.org/10.1074/jbc.M413379200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15831490"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15831490"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "H Kitagawa, H Shimakawa, K Sugahara "}, {"type": "b", "children": [{"type": "t", "text": "The tumor suppressor EXT-like gene EXTL2 encodes an alpha1, 4-N-acetylhexosaminyltransferase that transfers N-acetylgalactosamine and N-acetylglucosamine to the common glycosaminoglycan-protein linkage region. The key enzyme for the chain initiation of heparan sulfate."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (1999)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.274.20.13933"}], "href": "https://doi.org/10.1074/jbc.274.20.13933"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "10318803"}], "href": "https://pubmed.ncbi.nlm.nih.gov/10318803"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "B T Kim, H Kitagawa, J Tamura , et al. "}, {"type": "b", "children": [{"type": "t", "text": "Human tumor suppressor EXT gene family members EXTL1 and EXTL3 encode alpha 1,4- N-acetylglucosaminyltransferases that likely are involved in heparan sulfate/ heparin biosynthesis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Proc Natl Acad Sci U S A (2001)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1073/pnas.131188498"}], "href": "https://doi.org/10.1073/pnas.131188498"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "11390981"}], "href": "https://pubmed.ncbi.nlm.nih.gov/11390981"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Satomi Nadanaka, Shaobo Zhou, Shoji Kagiyama, et al. "}, {"type": "b", "children": [{"type": "t", "text": "EXTL2, a member of the EXT family of tumor suppressors, controls glycosaminoglycan biosynthesis in a xylose kinase-dependent manner."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M112.416909"}], "href": "https://doi.org/10.1074/jbc.M112.416909"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23395820"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23395820"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Satomi Nadanaka, Hiroshi Kitagawa "}, {"type": "b", "children": [{"type": "t", "text": "EXTL2 controls liver regeneration and aortic calcification through xylose kinase-dependent regulation of glycosaminoglycan biosynthesis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Matrix Biol (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.matbio.2013.10.010"}], "href": "https://doi.org/10.1016/j.matbio.2013.10.010"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24176719"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24176719"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Satomi Nadanaka, Hiroshi Kitagawa "}, {"type": "b", "children": [{"type": "t", "text": "Exostosin-like 2 regulates FGF2 signaling by controlling the endocytosis of FGF2."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochim Biophys Acta Gen Subj (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.bbagen.2018.01.002"}], "href": "https://doi.org/10.1016/j.bbagen.2018.01.002"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "29305908"}], "href": "https://pubmed.ncbi.nlm.nih.gov/29305908"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Xenia Kaidonis, Wan Chin Liaw, Ainslie Derrick Roberts, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Gene silencing of EXTL2 and EXTL3 as a substrate deprivation therapy for heparan sulphate storing mucopolysaccharidoses."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Eur J Hum Genet (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/ejhg.2009.143"}], "href": "https://doi.org/10.1038/ejhg.2009.143"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19690583"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19690583"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Kirankumar Katta, Tabasum Imran, Marta Busse-Wicher, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Reduced Expression of EXTL2, a Member of the Exostosin (EXT) Family of Glycosyltransferases, in Human Embryonic Kidney 293 Cells Results in Longer Heparan Sulfate Chains."}]}, {"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.M114.631754"}], "href": "https://doi.org/10.1074/jbc.M114.631754"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25829497"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25829497"}]}]}]}