{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n Integrin α3 (ITGA3) is a multifunctional adhesion receptor that plays pivotal roles in orchestrating cell–extracellular matrix interactions, thereby influencing cell adhesion, migration, and tissue organization. In the context of cancer, ITGA3 has been implicated as a key driver of tumor progression and metastasis. For example, in malignant melanoma, dysregulation of ITGA3 by microRNA‐214 affects cell movement, survival under anchorage–independent conditions, and ultimately metastatic colonization."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " Moreover, the subcellular localization and translation of ITGA3 are tightly controlled at the RNA level; the Muscleblind-like protein MLP1/MBNL2 binds specific motifs in the 3′‐UTR of ITGA3 transcripts to direct their localization to adhesion complexes, thereby ensuring proper assembly of the cell–matrix interface."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n ITGA3 also partners laterally with other membrane proteins. Its strong association with the tetraspanin CD151 enhances laminin binding (α3β1 integrin complex), which is critical for maintaining the structural integrity of basement membranes in epithelial tissues such as kidney podocytes."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": " In line with this, human patients harboring mutations in ITGA3 exhibit disrupted basement-membrane organization and compromised barrier functions in organs including the kidney, lung, and skin."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n In addition to its established roles in adhesion, ITGA3 contributes to the regulation of cell migration. ITGA3-containing integrin α3β1 complexes interact with urokinase-type plasminogen activator receptor (uPAR) to modulate adhesion to extracellular substrates such as vitronectin."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": " Further modulation of ITGA3 function occurs within specialized multi-molecular domains (“glycosynapses”) where its interaction with tetraspanin CD9 and the membrane ganglioside GM3 governs the balance between adhesion and motility—high levels of GM3 enhance ITGA3–CD9 interactions and are associated with reduced tumor cell invasiveness, whereas diminished GM3 levels correlate with increased cell motility."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n This pro-adhesive and pro-migratory behavior is further evidenced in head and neck squamous cell carcinoma, where the miR-199 family targets ITGA3. Knockdown of ITGA3 in this setting leads to a significant inhibition of cancer cell migration and invasion, underscoring its role in promoting an aggressive tumor phenotype."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Beyond cancer, ITGA3 is important during normal development. In epithelial tissues undergoing branching morphogenesis (such as in salivary gland development), loss of both ITGA3 and its partner integrin α6 recapitulates phenotypes observed with dysregulated basement membrane composition, indicating that ITGA3 contributes to tissue organization and cellular differentiation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": "\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Elisa Penna, Francesca Orso, Daniela Cimino, et al. "}, {"type": "b", "children": [{"type": "t", "text": "microRNA-214 contributes to melanoma tumour progression through suppression of TFAP2C."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "EMBO J (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/emboj.2011.102"}], "href": "https://doi.org/10.1038/emboj.2011.102"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21468029"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21468029"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Yair Adereth, Vincent Dammai, Nurgun Kose, et al. "}, {"type": "b", "children": [{"type": "t", "text": "RNA-dependent integrin alpha3 protein localization regulated by the Muscleblind-like protein MLP1."}]}, {"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/ncb1335"}], "href": "https://doi.org/10.1038/ncb1335"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16273094"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16273094"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Norman Sachs, Maaike Kreft, Marius A van den Bergh Weerman, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Kidney failure in mice lacking the tetraspanin CD151."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Cell Biol (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1083/jcb.200603073"}], "href": "https://doi.org/10.1083/jcb.200603073"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17015618"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17015618"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Cristina Has, Giuseppina Spartà, Dimitra Kiritsi, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Integrin α3 mutations with kidney, lung, and skin disease."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "N Engl J Med (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1056/NEJMoa1110813"}], "href": "https://doi.org/10.1056/NEJMoa1110813"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22512483"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22512483"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Ying Wei, Ralf-Peter Czekay, Liliane Robillard, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Regulation of alpha5beta1 integrin conformation and function by urokinase receptor binding."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Cell Biol (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1083/jcb.200404112"}], "href": "https://doi.org/10.1083/jcb.200404112"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15684035"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15684035"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Koji Mitsuzuka, Kazuko Handa, Makoto Satoh, et al. "}, {"type": "b", "children": [{"type": "t", "text": "A specific microdomain (\"glycosynapse 3\") controls phenotypic conversion and reversion of bladder cancer cells through GM3-mediated interaction of alpha3beta1 integrin with CD9."}]}, {"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.M505630200"}], "href": "https://doi.org/10.1074/jbc.M505630200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16103120"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16103120"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Keiichi Koshizuka, Toyoyuki Hanazawa, Naoko Kikkawa, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Regulation of ITGA3 by the anti-tumor miR-199 family inhibits cancer cell migration and invasion in head and neck cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer Sci (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/cas.13298"}], "href": "https://doi.org/10.1111/cas.13298"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28612520"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28612520"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Ivan T Rebustini, Vaishali N Patel, Julian S Stewart, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Laminin alpha5 is necessary for submandibular gland epithelial morphogenesis and influences FGFR expression through beta1 integrin signaling."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Dev Biol (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.ydbio.2007.04.031"}], "href": "https://doi.org/10.1016/j.ydbio.2007.04.031"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17601529"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17601529"}]}]}]}