Matrix BiologyPub Date : 2026-02-01Epub Date: 2025-12-11DOI: 10.1016/j.matbio.2025.12.002
Maria Giulia Bigotti , Andrea Brancaccio
{"title":"α-Dystroglycan at the ECM-Cell crossroad: emerging functions of its N-terminal domain","authors":"Maria Giulia Bigotti , Andrea Brancaccio","doi":"10.1016/j.matbio.2025.12.002","DOIUrl":"10.1016/j.matbio.2025.12.002","url":null,"abstract":"<div><div>Dystroglycan plays a crucial role for cell to extracellular matrix (ECM) adhesiveness in a plethora of different tissues and physio-pathological conditions. It belongs to the dystrophin-glycoprotein complex, whose overall structure has been recently solved, providing fundamental insight into the assembly of its various protein components, including the dystroglycan complex. This inspired us to embark in a timely “recollection journey” of our studies on the dystroglycan domain organization, mainly focusing on the targeted mutagenesis analysis of the α-dystroglycan’s N-terminal domain (α-DGN) that we have carried out during the last 30 years. The account of such a journey also reinforces a crucial notion in protein biochemistry: a single amino acid substitution can lead to a significantly improved stability of the whole protein. Over-stabilizing matrix proteins, and proteins in general, has positive repercussions for the study of their structural and functional properties, and it is a crucial tool for developing biotechnological applications. Here we discuss newly emerged data along a series of yet unresolved points concerning the biochemical features and biological role of α-DGN, as well as the possible biomedical use recently emerged for a stabilized single site-directed variant of this protein domain.</div></div>","PeriodicalId":49851,"journal":{"name":"Matrix Biology","volume":"143 ","pages":"Pages 83-88"},"PeriodicalIF":4.8,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145732377","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Matrix BiologyPub Date : 2026-02-01Epub Date: 2025-11-19DOI: 10.1016/j.matbio.2025.11.006
Tolg C , Price M , Leith S , Miller T , Pavanel H , A.C. Nelson , Hill KA , McCarthy JB , Turley EA
{"title":"High hyaluronan binding and RHAMM expression identify an invasive and metastatic subpopulation in androgen-resistant prostate cancer cells","authors":"Tolg C , Price M , Leith S , Miller T , Pavanel H , A.C. Nelson , Hill KA , McCarthy JB , Turley EA","doi":"10.1016/j.matbio.2025.11.006","DOIUrl":"10.1016/j.matbio.2025.11.006","url":null,"abstract":"<div><div>Hyaluronan (HA) metabolism in prostate cancer associates with androgen resistance and metastasis. We showed that binding of low molecular weight HA (≤250 kDa) to castration-resistant prostate cancer cells was heterogeneous with most cells binding low amounts of HA (HA<sup>low</sup>) while a minor subset bound higher amounts of this polysaccharide (HA<sup>high</sup>). HA<sup>high</sup> subsets, which were separated by FACS, were stably more metastatic in vivo than HA<sup>low</sup> comparators. Multiplexed flow cytometry analyses indicated that both subsets displayed similar expression of the HA receptor CD44 while an elevated RHAMM cell surface display was unique to HA<sup>high</sup> subsets. Genomic deletion of <em>RHAMM</em> using CRISPR-Cas9 editing reduced the detection of HA<sup>high</sup> subsets by 6mer but not 250 kDa HA fluorescent probes, and phenocopied the lower aggressive properties of HA<sup>low</sup> tumor cells. Few differences in the mutation landscape of <em>RHAMM</em><sup>+/+</sup> vs. <em>RHAMM</em><sup>-/-</sup> tumor cells were detected but pathway analyses of differentially expressed genes predicted <em>RHAMM</em>-loss altered extracellular matrix signaling. Transcriptomic analyses revealed that HA<sup>high</sup> subsets and <em>RHAMM<sup>+</sup></em><sup>/+</sup> PC3MLN4 cells shared high expression of follistatin (FST), an activin member of the TGF-β family that is clinically linked to metastases in PCA patients. A causal role for FST in <em>RHAMM</em><sup>+/+</sup> tumor cell aggression was assessed using motility as a surrogate marker of invasive capability. FST antibodies blocked <em>RHAMM</em><sup>+/+</sup> PC3MLN4 cell migration while conversely, recombinant FST protein rescued the migration deficit of <em>RHAMM</em><sup>-/-</sup> comparators. These results define a novel form of prostate cancer cell heterogeneity, identify a method for detecting and isolating highly metastatic subsets and highlight a novel RHAMM-regulated pathway that may be targeted to improve patient management by limiting metastasis.</div></div>","PeriodicalId":49851,"journal":{"name":"Matrix Biology","volume":"143 ","pages":"Pages 23-35"},"PeriodicalIF":4.8,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145559902","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Human mammary 3D spheroid models uncover the role of filopodia in breaching the basement membrane to facilitate invasion","authors":"Alain Corinus , Sophie Abélanet , Julia Dubreuil , Zhenyu Zhu , Sabrina Pisano , Christelle Boscagli , Anne-Sophie Gay , Delphine Debayle , Marin Truchi , Kevin Lebrigand , Sandra Lacas-Gervais , Frédéric Brau , Xavier Descombes , Patricia Rousselle , Michel Franco , Frédéric Luton","doi":"10.1016/j.matbio.2025.11.008","DOIUrl":"10.1016/j.matbio.2025.11.008","url":null,"abstract":"<div><div>Basement membranes (BM) are thin, nanoporous sheets of specialized extracellular matrix (ECM) that line epithelial tissues. They are dynamic structures that serve multiple key functions, as evidenced by numerous diseases, including cancer progression, that are associated with their alterations. Our understanding of the BM and its communication with adjoining epithelial cells remains highly fragmented due to the BM’s complex molecular architecture, the lack of molecular tools, limitations in utilizing high-resolution imaging techniques to BMs assembled on tissues, and the difficulty of assessing their functional contributions <em>in vivo</em>. Here, by combining multiple -omics analyses and advanced microscopy methodologies, we characterized the BM from two normal human mammary epithelial cell lines, MCF10 and HMLE, grown as spheroids in 3D matrices. Our findings indicate that the spheroids autonomously assemble a BM exhibiting all the molecular, structural, and biophysical characteristics of physiological BM. Using these minimalist model systems, we provide evidence that collagen IV, laminins, perlecan, and hemidesmosomes all overlap in a shared porous lattice. Next, we demonstrate that the invasion-promoting <em>PSD4</em>/EFA6B knockout, found in patients with breast cancer, decreases the expression of BM components and their assembly on the spheroid surface. We then show that invasive spheroids develop enlarged pores in the BM via filopodia-like plasma membrane extensions, which further expand in a protease-dependent manner, thereby facilitating the passage of invasive cells.</div></div>","PeriodicalId":49851,"journal":{"name":"Matrix Biology","volume":"143 ","pages":"Pages 36-47"},"PeriodicalIF":4.8,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145657542","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Matrix BiologyPub Date : 2026-02-01Epub Date: 2025-11-26DOI: 10.1016/j.matbio.2025.11.007
Andrew Leask
{"title":"CCN1: a SASPy protein that plays multifaceted roles in fibrogenesis","authors":"Andrew Leask","doi":"10.1016/j.matbio.2025.11.007","DOIUrl":"10.1016/j.matbio.2025.11.007","url":null,"abstract":"<div><div>The matricellular protein CCN1 is pro-senescent, and can be considered as a possible inducer of the senescence-associated secretory phenotype (SASP). Although the SASP facilitates healthy tissue repair when senescent cells are properly cleared, pathological fibrosis results when this clearance is defective. Similarly, CCN1 can have both anti-fibrotic and pro-fibrotic properties, depending on the context. Recent data indicate that although CCN1 has anti-fibrotic roles in normal tissue repair and the liver, it also has pro-fibrotic roles in lung, kidney, cardiac, skin and liver fibrosis/scarring. That CCN1 has context-dependent roles in fibrosis deserves consideration when developing anti-fibrotic drugs.</div></div>","PeriodicalId":49851,"journal":{"name":"Matrix Biology","volume":"143 ","pages":"14"},"PeriodicalIF":4.8,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145598946","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Laminin-511-functionalized fibrin gel enables in-gel proliferation of human induced pluripotent stem cells","authors":"Yukimasa Taniguchi, Mamoru Takizawa, Ayaka Hada, Ayano Ishimaru, Kiyotoshi Sekiguchi","doi":"10.1016/j.matbio.2025.10.003","DOIUrl":"10.1016/j.matbio.2025.10.003","url":null,"abstract":"<div><div>Fibrin is a biocompatible hydrogel that is widely used as a surgical sealant and as a scaffold for in vitro cell culture. Here, we engineered a heterotrimeric chimera between fibrinogen and laminin-511 by connecting the N-terminal self-polymerization domain of fibrinogen with the C-terminal integrin-binding domain of laminin-511 via their coiled-coil regions. The resulting chimeric protein, designated Chimera-511, binds to fibrinogen in a thrombin-dependent manner and exerts integrin-binding activity in a fibrin(ogen)-bound form. Chimera-511 co-polymerizes with fibrinogen to form a fibrin gel endowed with the potent integrin-binding activity of laminin-511, thereby enabling robust three-dimensional proliferation of human induced pluripotent stem cells while maintaining their pluripotency marker expression and trilineage differentiation potential. This functionalized, biodegradable fibrin gel provides a defined and clinically compatible three-dimensional scaffold for stem cell culture, with potential applications in both basic research and regenerative medicine.</div></div>","PeriodicalId":49851,"journal":{"name":"Matrix Biology","volume":"142 ","pages":"Pages 21-32"},"PeriodicalIF":4.8,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145276414","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Matrix BiologyPub Date : 2025-12-01Epub Date: 2025-11-13DOI: 10.1016/j.matbio.2025.11.002
Amina Baker , Mohammad Al Tarrass , Christos Chatziantoniou , Renata Kozyraki
{"title":"FAM20C and FAM20A in normal and ectopic mineralization: A focus on oro-renal syndromes","authors":"Amina Baker , Mohammad Al Tarrass , Christos Chatziantoniou , Renata Kozyraki","doi":"10.1016/j.matbio.2025.11.002","DOIUrl":"10.1016/j.matbio.2025.11.002","url":null,"abstract":"<div><div>FAM20C is part of the FAM20 family and is crucial for phosphorylating secreted proteins. It plays roles in various biological processes, including cellular calcium regulation and cardiovascular function. Pathogenic variants of <em>FAM20C</em> cause Raine syndrome, resulting in osteosclerotic dysplasia or hypophosphatemic rickets. Its paralog, FAM20A, is a secreted pseudokinase needed for optimal FAM20C activity. Mutations in <em>FAM20A</em> cause Enamel-Renal Syndrome. Common features in both syndromes include Amelogenesis Imperfecta, gingival fibromatosis and ectopic mineralization. We summarize current knowledge about the activity, interactions and regulation of FAM20C and FAM20A, with a focus on the possible role of bioactive lipids like sphingosine in activating FAM20C. We highlight the involvement of FAM20A and FAM20C in gingival fibromatosis, a fibrocalcifying disorder directly linked to the dysfunction of these proteins and the underlying molecular mechanisms. Additionally, we provide an overview of how FAM20C and FAM20A influence calcium homeostasis and mineralization. Since FAM20C-mediated phosphorylation is crucial in oral health, we detail how specific substrates such as osteopontin, periostin, or fetuin contribute to normal and ectopic mineralization and periodontal health. Although many questions about the roles of FAM20A and FAM20C in both oral and systemic diseases remain unresolved, targeting their activities could offer promising therapeutic options.</div></div>","PeriodicalId":49851,"journal":{"name":"Matrix Biology","volume":"142 ","pages":"Pages 58-85"},"PeriodicalIF":4.8,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145530804","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Matrix BiologyPub Date : 2025-12-01Epub Date: 2025-10-01DOI: 10.1016/j.matbio.2025.09.005
Taina Pihlajaniemi
{"title":"Transmembrane and multiplexin collagens in development and pathobiology","authors":"Taina Pihlajaniemi","doi":"10.1016/j.matbio.2025.09.005","DOIUrl":"10.1016/j.matbio.2025.09.005","url":null,"abstract":"<div><div>At its best, it is exhilarating to make unexpected discoveries when addressing carefully formed scientific hypotheses. This review depicts my scientific journey in the field of extracellular matrix biology, and more specifically in collagen research, starting in 1978 and continuing with exciting findings up to the present day. While recounting my early work on the enzymes of collagen biosynthesis, the focus will be on our discoveries of new types of nonfibrillar collagen: type XIII collagen, belonging to the MACIT subgroup among the collagen family of proteins, and types XV and XVIII collagens, constituting the multiplexin subgroup. We have investigated these collagens through molecular biological approaches in order to define their primary structures, and through biochemical and cell biological work to understand their special molecular properties. Furthermore, the generation of many mouse models has led us to exciting studies of the roles of these collagens in adipose tissue, bone, eye, heart, kidney, liver, peripheral nerves, skin, and cancer models, although it has of course also been rather daunting in terms of choosing the correct approach for each tissue. The work on animal models has nevertheless resulted in a broad understanding of the <em>in vivo</em> significance of these collagens, forming a fruitful basis for studying their relevance to human diseases, including malignant processes. Our conclusions have been that these collagens can contribute to the stability of the extracellular matrix and tissue structures, <em>e.g.,</em> the basement membrane and the adjacent fibrillar matrix in the case of the multiplexins and the motor synapse in the case of the MACIT type XIII collagen, and more unexpectedly, that they possess major roles as extrinsic regulators of the fates and functions of cells.</div></div>","PeriodicalId":49851,"journal":{"name":"Matrix Biology","volume":"142 ","pages":"Pages 11-20"},"PeriodicalIF":4.8,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145226241","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Matrix BiologyPub Date : 2025-12-01Epub Date: 2025-11-04DOI: 10.1016/j.matbio.2025.11.001
Anna M. Knapinska , Dorota Tokmina-Roszyk , Sabrina Haag , Jordan K. Lauer-Fields , Chandani Singh , Roma Stawikowska , Yibo He , Johan Askling , Rikard Holmdahl , Gregg B. Fields
{"title":"Matrix metalloproteinase 13 (MMP-13) processing of type II collagen is altered by antibodies and citrullination found in the early stages of rheumatoid arthritis","authors":"Anna M. Knapinska , Dorota Tokmina-Roszyk , Sabrina Haag , Jordan K. Lauer-Fields , Chandani Singh , Roma Stawikowska , Yibo He , Johan Askling , Rikard Holmdahl , Gregg B. Fields","doi":"10.1016/j.matbio.2025.11.001","DOIUrl":"10.1016/j.matbio.2025.11.001","url":null,"abstract":"<div><div>A subset of rheumatoid arthritis (RA) is the production of autoantibodies, including antibodies to citrullinated proteins (ACPA) and antibodies to type II collagen (AC2A). Type II collagen (COL2) is the major protein in joint cartilage and is a target of arthritogenic autoantibodies. We could confirm that sera from RA patients react with both citrullinated and native triple-helical COL2 epitopes. We examined the modulation of COL2 processing by matrix metalloproteinase 13 (MMP-13), the main collagenase responsible for degradation of articular cartilage. Anti-COL2 antibodies (AC2A) targeting the C1 epitope (residues 359–363) partially inhibited intact COL2 and fragment hydrolysis, resulting in two distinct fragments in the 25–30 kDa range. The AC2A targeting the E10 epitope (residues 777–783, the region where MMP-13 initially cleaves COL2) partially inhibited intact COL2 and fragment hydrolysis, resulting in a distinct fragment of ∼30 kDa. The AC2As targeting the F4 epitope (residues 932–936) partially inhibited collagen fragment hydrolysis, resulting in four distinct fragments in the 20–30 kDa range. Sequencing of isolated fragments revealed 14 terminated cleavage sites. Citrullination of the COL2 cleavage site reduced MMP-13 efficiency, which should further exacerbate fragment production rather than complete digestion. The results indicated that, under normal maintenance, MMP-13 cleaves COL2 initially at the 775–776 bond, followed by further digestion of COL2 fragments. Citrullination slows the initial processing of COL2 by MMP-13. In concert, AC2As inhibit the action of MMP-13 at different stages, resulting in production of collagen fragments differing in composition encountered under normal circumstances. The abnormal COL2 fragments could activate the immune system to be more pathogenic or regulatory as well as modify chondrocyte functions, and thereby play a role in the initiation of RA.</div></div>","PeriodicalId":49851,"journal":{"name":"Matrix Biology","volume":"142 ","pages":"Pages 46-57"},"PeriodicalIF":4.8,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145441808","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Matrix BiologyPub Date : 2025-12-01Epub Date: 2025-10-03DOI: 10.1016/j.matbio.2025.10.001
Dalila Di Francesco , Diego Mantovani , George Hussey , Francesca Boccafoschi
{"title":"Matrix bound nanovesicles: A great promise for TERM in less than a decade of research","authors":"Dalila Di Francesco , Diego Mantovani , George Hussey , Francesca Boccafoschi","doi":"10.1016/j.matbio.2025.10.001","DOIUrl":"10.1016/j.matbio.2025.10.001","url":null,"abstract":"<div><div>Decellularized extracellular matrix materials have been widely studied for tissue engineering and regenerative medicine (TERM) applications, largely because of their intrinsic bioactivity and immunomodulatory potentials. These properties confer decellularized extracellular matrix biomaterials a biological advantage over other biomaterials, especially synthetic ones, leading to several successful applications in TERM. While the complex composition of decellularized materials is well known and thought to play a role in providing the regenerative advantage, the fine mechanisms laying behind their bioactivity and immunomodulation were not fully understood yet. In the last decade, researchers have discovered a novel component in decellularized extracellular matrix materials: the matrix bound nanovesicle (MBV). This newly described type of extracellular vesicle is characterized by a tight relation to the extracellular matrix, differently from other liquid phase vesicles, and presents a unique tissue specific cargo, thought to be secreted by cells for specific cell signalling purposes. Although other extracellular vesicles subtypes have been extensively studied in past years, MBVs are different in many ways, making this research field noticeably young. Major bioactivity and immune modulating ability are key features of MBVs that were evident right from the first research works. However, to understand how MBVs can recapitulate and confer decellularized biomaterials with their signature biological performance, they are being characterized in depth. In particular, their rich and varied cargo is being explored, which has shown to play a fundamental role in MBVs’ biological potential. This discovery not only revolutionized the look on decellularized extracellular matrix materials, but it also opened the way for research on a novel type of biomaterial, with plenty potential in therapeutical and regenerative applications. This review presents in detail what has been discovered up to now on MBVs, their properties, biological roles, and potential in TERM.</div></div>","PeriodicalId":49851,"journal":{"name":"Matrix Biology","volume":"142 ","pages":"Pages 1-10"},"PeriodicalIF":4.8,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145229938","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Matrix BiologyPub Date : 2025-12-01Epub Date: 2025-10-17DOI: 10.1016/j.matbio.2025.10.004
Asher R. Utz , Linlin Ma , Dalton Hilovsky , Brenna M. Zimmer , Emily Allego , Jade Fluharty , Pooja Narasimhan , Jeffrey R. Enders , George Grady , Monica Milici , Pengda Liu , Xiaojing Liu , Joseph J. Barycki , Melanie A. Simpson
{"title":"Phosphorylation of UDP-glucose dehydrogenase increases glycosaminoglycan biosynthesis and promotes tumor cell motility, spheroid growth, and therapeutic resistance","authors":"Asher R. Utz , Linlin Ma , Dalton Hilovsky , Brenna M. Zimmer , Emily Allego , Jade Fluharty , Pooja Narasimhan , Jeffrey R. Enders , George Grady , Monica Milici , Pengda Liu , Xiaojing Liu , Joseph J. Barycki , Melanie A. Simpson","doi":"10.1016/j.matbio.2025.10.004","DOIUrl":"10.1016/j.matbio.2025.10.004","url":null,"abstract":"<div><div>UDP-glucose 6-dehydrogenase (UGDH) is an essential enzyme that catalyzes the oxidation of UDP-glucose to UDP-glucuronate. UGDH is elevated in multiple cancers, including prostate cancer, and is functionally implicated in castration resistant recurrence. UGDH is composed of three dimeric units that associate stably as a hexamer in cellular conditions. The dynamic reorganization of noncovalent interactions at the dimer contact interfaces is essential for UGDH activity. In this study, we examined the functional relevance of a putative AGC kinase motif located at the dimer-dimer interface. We demonstrated that UGDH is phosphorylated in LNCaP cells, specifically at serine 316, by RSK2, p70S6K, and SGK1. To determine the functional implications of UGDH S316 phosphorylation, we generated and characterized phosphomimetic (S316D) and phosphodeficient (S316A) point mutations. Intrinsic properties of the purified recombinant proteins were only modestly affected by the substitutions. The stable overexpression of UGDH S316D in LNCaP cells significantly increased the rate of N- and O-glycan synthesis, as well as the production of hyaluronan and sulfated glycosaminoglycans, while reducing DHT glucuronidation, resulting in significant increases in growth of tumor spheroids, cell proliferation and motility, and resistance to enzalutamide. In contrast, UGDH S316A expression reduced the production of glycans and glycosaminoglycans, restored DHT glucuronidation, and impaired growth and motility. Overall, our results support UGDH phosphorylation as a point of control for intracellular and cell surface glycan production, thereby regulating cell proliferation, anchorage dependence, motility, and tumor cell therapeutic resistance.</div></div>","PeriodicalId":49851,"journal":{"name":"Matrix Biology","volume":"142 ","pages":"Pages 33-45"},"PeriodicalIF":4.8,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145330702","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}