Hyaluronan Synthases: A Decade-plus of Novel Glycosyltransferases

Weigel, Paul H.; DeAngelis, Paul L.

doi:10.1074/jbc.r700036200

Cited by 302 publications

(289 citation statements)

References 71 publications

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“…It should be noted, however, that hyaluronan is secreted through the plasma membrane in conjunction with its synthesis and that HAS isoforms are rather small transmembrane proteins; possibly more than one HAS molecule is needed to form a pore through which hyaluronan is extruded. Notably, there are indications that phospholipids, such as cardiolipin, are required for Streptococcus pyogenes HAS activity (38,39). It is possible that the activity of mammalian HAS can also be affected by the lipids in the plasma membrane.…”

Section: Discussionmentioning

confidence: 99%

The Activity of Hyaluronan Synthase 2 Is Regulated by Dimerization and Ubiquitination

Karousou

Kamiryo

Skandalis

et al. 2010

Journal of Biological Chemistry

112

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Hyaluronan is a component of the extracellular matrix, which affects tissue homeostasis. In this study, we investigated the regulatory mechanisms of one of the hyaluronan-synthesizing enzymes, HAS2. Ectopic expression of Flag-and 6myc-HAS2 in COS-1 cells followed by immunoprecipitation and immunoblotting revealed homodimers; after co-transfection with Flag-HAS3, also heterodimers were seen. Furthermore, the expressed HAS2 was ubiquitinated. We identified one acceptor site for ubiquitin on lysine residue 190. Mutation of this residue led to inactivation of the enzymatic activity of HAS2. Interestingly, K190R-mutated HAS2 formed dimers with wt HAS2 and quenched the activity of wt HAS2, thus demonstrating a functional role of the dimeric configuration.Hyaluronan is abundantly found in tissues throughout the body and has key roles in tissue organization and homeostasis (1). Abnormal accumulation of hyaluronan in tissues and serum is associated with the progression of many diseases, such as inflammatory diseases and cancer (2-5). The biosynthesis of hyaluronan is tightly regulated by growth factors and cytokines as well as other stimuli that promote wound healing, inflammation, or transformation. External regulatory signals, such as platelet-derived growth factor (PDGF)-BB, transforming growth factor (TGF)-␤, and phorbol 12-myristate 13-acetate (PMA), regulate both the size (6) and amount of the produced hyaluronan (7-14).The hyaluronan-synthesizing enzymes (HAS) 4 were cloned and characterized first in the bacterium Streptococcus pyogenes, and then in mammals, where three different HAS isoforms were characterized, HAS1, HAS2, and HAS3 (15, 16). Studies by us and other laboratories (6, 11) revealed that growth factormediated increase of hyaluronan synthesis is often due to induction of the HAS2 gene in fibroblasts, whereas external signals have been shown to predominantly regulate HAS1 and HAS3 transcripts in synoviocytes and keratinocytes, respectively (12,14,17). In addition to the regulation of HASs at the transcriptional level (6,11,13,14), there is evidence that the activity of HAS isoforms is regulated by phosphorylation by protein kinase C (PKC), protein kinase A (PKA), calcium-dependent protein kinase, and extracellular signal-regulated kinase (10, 18 -20). Prediction from their amino acid sequences suggests that HASs are multi-pass membrane proteins (15) that occur in the plasma membrane, but there are also evidence that much of the HAS enzymes reside at intracellular localizations including perinuclear membrane, endoplasmic reticulum (ER)-Golgi pathway, and endocytic vesicles (21-23).Ubiquitination of proteins affects their stability, activity, interaction with other proteins as well as subcellular localization and trafficking (24, 25). Modification of a protein with K48-linked poly-Ub chains can trigger the proteasomal degradation of the protein. The functional consequences of protein ubiquitination by K63-linked poly-Ub chains include activation of proteins or alteration of their trafficking. Protein modi...

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Section: Discussionmentioning

confidence: 99%

The Activity of Hyaluronan Synthase 2 Is Regulated by Dimerization and Ubiquitination

Karousou

Kamiryo

Skandalis

et al. 2010

Journal of Biological Chemistry

112

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“…This residue is within the large cytoplasmic loop of HAS2 that has been described to be critical for enzyme activity (47). This covalent post-translational modification strongly augments HA synthetic capability.…”

Section: Discussionmentioning

confidence: 99%

Role of UDP-N-Acetylglucosamine (GlcNAc) and O-GlcNAcylation of Hyaluronan Synthase 2 in the Control of Chondroitin Sulfate and Hyaluronan Synthesis

Vigetti

Deleonibus

Moretto

et al. 2012

Journal of Biological Chemistry

127

105

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Background: UDP-GlcNAc is a precursor of glycoconjugates, including hyaluronan, and induces protein glycosylation to form O-linked GlcNAc (O-GlcNAcylation). Results: UDP-GlcNAc induces hyaluronan synthesis through O-GlcNAcylation of hyaluronan synthase 2, which stabilizes the enzyme and prevents its proteasomal degradation. Conclusion: O-GlcNAcylation of hyaluronan synthase 2 can control synthesis of extracellular matrices with hyaluronan. Significance: UDP-GlcNAc could control cell microenvironments that are altered in many pathologies, including vascular diseases and cancer.

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“…However, CD44 is endogenously expressed at low levels in healthy tissues; 17 because of this expression, side effects still occur. 18,19 Antibody targeted therapies are effective in cancer treatments for three principal reasons: (1) The epitope recognized by the antibody is over-expressed on the tumor cell. (2) The antibody has better access to the tumor than to normal tissues that also express the epitope.…”

Section: Targeting To Cd44 With Anti-cd44 Antibodies or Hyaluronanmentioning

confidence: 99%

Anticancer Therapeutics: Targeting Macromolecules and Nanocarriers to Hyaluronan or CD44, a Hyaluronan Receptor

2008

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The complex system involved in the synthesis, degradation, and binding of the high molecular weight glycosaminoglycan hyaluronic acid (hyaluronan or HA) provides a variety of structures that can be exploited for targeted cancer therapy. In many cancers of epithelial origin there is an up-regulation of CD44, a receptor that binds HA. In other cancers, HA in the tumor matrix is over-expressed. Both CD44 on cancer cells and HA in the matrix have been targets for anti-cancer therapy. Even though CD44 is expressed in normal epithelial cells and HA is part of the matrix of normal tissues, selective targeting to cancer is possible. This is because macromolecular carriers predominantly extravasate into the tumor and not normal tissue; thus CD44-HA targeted carriers administered intravenously localize preferentially into tumors. Anti-CD44 antibodies have been used in patients to deliver radioisotopes or mertansine for treatment of CD44 expressing tumors. In early phase clinical trials, patients with breast or head and neck tumors treated with anti-CD44 conjugates experienced stabilized disease. A dose-limiting toxicity was associated with distribution of the antibody-drug conjugate to the skin, a site in the body with a high level of CD44. HA has been used as a drug carrier and a ligand on liposomes or nanoparticles to target drugs to CD44 over-expressing cells. Drugs can be attached to HA via the carboxylate on the glucuronic acid residue, the hydroxyl on the Nacetylglucosamine, or the reducing end which are located on a repeating disaccharide. Drugs delivered in HA-modified liposomes exhibited excellent anti-tumor activity both in vitro and in murine tumor models. The HA matrix is also a potential target for anti-cancer therapies. By manipulating the interaction of HA with cell surface receptors, either by degrading it with hyaluronidase or by interfering with CD44-HA interactions using soluble CD44 proteins, tumor progression was blocked. Finally, cytotoxic drugs or pro-drug converting enzymes can be attached to the HA matrix to generate a cytotoxic fence around the tumor. This review describes how the complex interplay among cancer biology, the CD44-HA interaction, drug carriers and drug targeting has been used to improve anti-cancer therapies. As these approaches evolve, they hold forth the prospect of significantly improved targeted anti-cancer treatments. KeywordsAntibody; Biodistribution; Cancer; Chemotherapy; Drug-conjugate; EPR effect; Liposome; Polymer; Prodrug; Recombinant Protein The Biology of the CD44-Hyaluronan InteractionHyaluronan (HA) (Figure 1) is a high molecular weight glycosaminoglycan, extracellular matrix component essential for proper cell growth, organ structural stability, and tissue organization. The amount of HA in a tissue depends upon on a complex interplay among HA synthesis by HA synthases, 1 HA internalization by cell surface receptors, 2 Interference with the CD44-HA interaction by either targeting drugs to CD44, 14 targeting drugs to the HA matrix 15 or interfering with HA ma...

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Hyaluronan Synthases: A Decade-plus of Novel Glycosyltransferases

Cited by 302 publications

References 71 publications

The Activity of Hyaluronan Synthase 2 Is Regulated by Dimerization and Ubiquitination

The Activity of Hyaluronan Synthase 2 Is Regulated by Dimerization and Ubiquitination

Role of UDP-N-Acetylglucosamine (GlcNAc) and O-GlcNAcylation of Hyaluronan Synthase 2 in the Control of Chondroitin Sulfate and Hyaluronan Synthesis

Anticancer Therapeutics: Targeting Macromolecules and Nanocarriers to Hyaluronan or CD44, a Hyaluronan Receptor

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