{"doi":"10.1016/j.jbc.2021.100481","title":"The cell surface hyaluronidase TMEM2 regulates cell adhesion and migration via degradation of hyaluronan at focal adhesion sites","abstract":"The extracellular matrix (ECM) plays an important role in maintaining tissue homeostasis and poses a significant physical barrier to in vivo cell migration. Accordingly, as a means of enhancing tissue invasion, tumor cells use matrix metalloproteinases to degrade ECM proteins. However, the in vivo ECM is comprised not only of proteins but also of a variety of nonprotein components. Hyaluronan (HA), one of the most abundant nonprotein components of the interstitial ECM, forms a gel-like antiadhesive barrier that is impenetrable to particulate matter and cells. Mechanisms by which tumor cells penetrate the HA barrier have not been addressed. Here, we demonstrate that transmembrane protein 2 (TMEM2), the only known transmembrane hyaluronidase, is the predominant mediator of contact-dependent HA degradation and subsequent integrin-mediated cell–substrate adhesion. We show that a variety of tumor cells are able to eliminate substrate-bound HA in a tightly localized pattern corresponding to the distribution of focal adhesions (FAs) and stress fibers. This FA-targeted HA degradation is mediated by TMEM2, which itself is localized at site of FAs. TMEM2 depletion inhibits the ability of tumor cells to attach and migrate in an HA-rich environment. Importantly, TMEM2 directly binds at least two integrins via interaction between extracellular domains. Our findings demonstrate a critical role for TMEM2-mediated HA degradation in the adhesion and migration of cells on HA-rich ECM substrates and provide novel insight into the early phase of FA formation. The extracellular matrix (ECM) plays an important role in maintaining tissue homeostasis and poses a significant physical barrier to in vivo cell migration. Accordingly, as a means of enhancing tissue invasion, tumor cells use matrix metalloproteinases to degrade ECM proteins. However, the in vivo ECM is comprised not only of proteins but also of a variety of nonprotein components. Hyaluronan (HA), one of the most abundant nonprotein components of the interstitial ECM, forms a gel-like antiadhesive barrier that is impenetrable to particulate matter and cells. Mechanisms by which tumor cells penetrate the HA barrier have not been addressed. Here, we demonstrate that transmembrane protein 2 (TMEM2), the only known transmembrane hyaluronidase, is the predominant mediator of contact-dependent HA degradation and subsequent integrin-mediated cell–substrate adhesion. We show that a variety of tumor cells are able to eliminate substrate-bound HA in a tightly localized pattern corresponding to the distribution of focal adhesions (FAs) and stress fibers. This FA-targeted HA degradation is mediated by TMEM2, which itself is localized at site of FAs. TMEM2 depletion inhibits the ability of tumor cells to attach and migrate in an HA-rich environment. Importantly, TMEM2 directly binds at least two integrins via interaction between extracellular domains. Our findings demonstrate a critical role for TMEM2-mediated HA degradation in the adhesion and migration of cells on HA-rich ECM substrates and provide novel insight into the early phase of FA formation. Hyaluronan (HA) is a high–molecular weight polysaccharide belonging to the family of glycosaminoglycans. It is a long unbranched polymer composed of repeating disaccharide units of a N-acetylglucosamine and a glucuronic acid, with a molecular weight reaching as high as 107 Da (1Laurent T.C. Fraser J.R. Hyaluronan.FASEB J. 1992; 6: 2397-2404Crossref PubMed Scopus (2012) Google Scholar). Because of its highly hydrophilic nature, HA has an extremely large hydrodynamic volume in solution and assumes semiflexible secondary and tertiary conformations based on intramolecular and intermolecular hydrogen bonding (2Scott J.E. Heatley F. Hyaluronan forms specific stable tertiary structures in aqueous solution: A 13C NMR study.Proc. Natl. Acad. Sci. U. S. A. 1999; 96: 4850-4855Crossref PubMed Scopus (194) Google Scholar, 3Cowman M.K. Schmidt T.A. Raghavan P. Stecco A.","journal":"Journal of Biological Chemistry","year":2021,"id":162110,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":50,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9552,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":678350,"name":"Yuki Tobisawa","orcid":"0000-0001-8026-9541","position":1,"is_corresponding":false},{"id":679337,"name":"Ayako Murao","orcid":null,"position":2,"is_corresponding":false},{"id":678351,"name":"Hayato Yamamoto","orcid":"0000-0002-4557-0619","position":3,"is_corresponding":false},{"id":581057,"name":"Chikara Οhyama","orcid":"0000-0003-1550-8379","position":4,"is_corresponding":false},{"id":382727,"name":"Yu Yamaguchi","orcid":"0000-0003-0098-281X","position":5,"is_corresponding":false},{"id":678349,"name":"Fumitoshi Irie","orcid":"0000-0001-6363-7808","position":0,"is_corresponding":true}],"reference_count":45,"raw_metadata":null,"created_at":"2026-07-18T23:45:00.600065Z","pmid":"33647313","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}