Glycosyltransferases EXTL2 and EXTL3 cellular balance dictates heparan sulfate biosynthesis and shapes gastric cancer cell motility and invasion

Marques, Catarina; Poças, Juliana; Gomes, Catarina; Faria‐Ramos, Isabel; Reis, Celso A.; Vivès, Romain R.; Magalhães, Ana

doi:10.1016/j.jbc.2022.102546

Cited by 7 publications

(3 citation statements)

References 76 publications

(81 reference statements)

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“…4a). This result may explain why the deletion of EXTL3 in cells leads to a complete loss of HS synthesis 11,32 . Incubation of GlcNAc-TetraP-BETA with EXTL3 or EXT1/EXT2 and UDP-GlcA resulted in a single product peak, demonstrating that both enzymes are able to catalyse the addition of a sixth sugar, forming GlcA-GlcNAc-TetraP-BETA (Fig.…”

Section: Polymerisation Of Hs and Cs Backbones In Vitromentioning

confidence: 98%

Molecular mechanism of decision-making in glycosaminoglycan biosynthesis

Sammon,

Krueger,

Busse-Wicher

et al. 2023

Nat Commun

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Two major glycosaminoglycan types, heparan sulfate (HS) and chondroitin sulfate (CS), control many aspects of development and physiology in a type-specific manner. HS and CS are attached to core proteins via a common linker tetrasaccharide, but differ in their polymer backbones. How core proteins are specifically modified with HS or CS has been an enduring mystery. By reconstituting glycosaminoglycan biosynthesis in vitro, we establish that the CS-initiating N-acetylgalactosaminyltransferase CSGALNACT2 modifies all glycopeptide substrates equally, whereas the HS-initiating N-acetylglucosaminyltransferase EXTL3 is selective. Structure-function analysis reveals that acidic residues in the glycopeptide substrate and a basic exosite in EXTL3 are critical for specifying HS biosynthesis. Linker phosphorylation by the xylose kinase FAM20B accelerates linker synthesis and initiation of both HS and CS, but has no effect on the subsequent polymerisation of the backbone. Our results demonstrate that modification with CS occurs by default and must be overridden by EXTL3 to produce HS.

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Section: Polymerisation Of Hs and Cs Backbones In Vitromentioning

confidence: 98%

Molecular mechanism of decision-making in glycosaminoglycan biosynthesis

Sammon,

Krueger,

Busse-Wicher

et al. 2023

Nat Commun

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“…HS elongation starts with the addition of a GlcNAc residue to the linker catalyzed by exostosin‐like 3 (EXTL3). Another exostosin family member, EXTL‐2, acts as a negative regulator of heparan sulfate (HS) biosynthesis through a mechanism that remains to be clarified [49]. Following the addition of this first GlcNAc, the polymerization of the proheparan chain occurs through the alternative addition of GlcA and GLcNAc residues by exostosins EXT1 and EXT2.…”

Section: Gag Biosynthetic Pathwaysmentioning

confidence: 99%

“…The lack of EXTL2 enzymatic activity results in the remodeling of GAGs on gastric cancer cell glycocalyx, promoting syndecan‐4 expression and overproduction of HS with an altered sulfation profile. These changes promote a more aggressive and invasive phenotype [49].…”

Section: Gags and Their Protein Moieties In Diseasementioning

confidence: 99%

A biological guide to glycosaminoglycans: current perspectives and pending questions

Ricard‐Blum,

Vivès,

Schaefer

et al. 2024

The FEBS Journal

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Mammalian glycosaminoglycans (GAGs), except hyaluronan (HA), are sulfated polysaccharides that are covalently attached to core proteins to form proteoglycans (PGs). This article summarizes key biological findings for the most widespread GAGs, namely HA, chondroitin sulfate/dermatan sulfate (CS/DS), keratan sulfate (KS), and heparan sulfate (HS). It focuses on the major processes that remain to be deciphered to get a comprehensive view of the mechanisms mediating GAG biological functions. They include the regulation of GAG biosynthesis and postsynthetic modifications in heparin (HP) and HS, the composition, heterogeneity, and function of the tetrasaccharide linkage region and its role in disease, the functional characterization of the new PGs recently identified by glycoproteomics, the selectivity of interactions mediated by GAG chains, the display of GAG chains and PGs at the cell surface and their impact on the availability and activity of soluble ligands, and on their move through the glycocalyx layer to reach their receptors, the human GAG profile in health and disease, the roles of GAGs and particular PGs (syndecans, decorin, and biglycan) involved in cancer, inflammation, and fibrosis, the possible use of GAGs and PGs as disease biomarkers, and the design of inhibitors targeting GAG biosynthetic enzymes and GAG–protein interactions to develop novel therapeutic approaches.

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Hippo cell signaling and HS-proteoglycans regulate tissue form and function, age-dependent maturation, extracellular matrix remodeling, and repair

Melrose

2024

American Journal of Physiology-Cell Physiology

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This review examined how Hippo cell signaling and HS-proteoglycans (HSPGs) regulate tissue form and function. Despite being a non-weight bearing tissue the brain is regulated by Hippo mechanoresponsive cell signalling pathways during embryonic development. HS-proteoglycans interact with growth factors, morphogens and extracellular matrix components to regulate development and pathology. Pikachurin and Eyes Shut interact with dystroglycan to stabilize the photoreceptor axoneme primary cilium and ribbon synapse facilitating phototransduction and neurotransduction with bipolar retinal neuronal networks in ocular vision, the primary human sense. Another HSPG, Neurexin interacts with structural and adaptor proteins to stabilize synapses and ensure specificity of neural interactions, and aids in synaptic potentiation and plasticity in neurotransduction. HSPGs also stabilize the blood brain barrier and motor neuron basal structures in the neuromuscular junction. Agrin and perlecan localize acetylcholinesterase and its receptors in the neuromuscular junction essential for neuromuscular control. The primary cilium is a mechanosensory hub on neurons, utilized by YAP-TAZ Hippo, Hh, Wnt, TGF-b/BMP receptor tyrosine kinase cell signaling. Members of the glypican HSPG proteoglycan family interact with Smoothened and Patched G-protein coupled receptors on the cilium to regulate Hh and Wnt signaling during neuronal development. Control of glycosyl sulfotransferases and endogenous protease expression by Hippo TAZ YAP represents a mechanism whereby the fine structure of HS-proteoglycans can be potentially modulated spatio-temporally to regulate tissue morphogenesis in a similar manner to how Hippo signaling controls sialyltransferase expression and mediation of cell-cell recognition, dysfunctional sialic acid expression is a feature of many tumors.

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Glycosyltransferases EXTL2 and EXTL3 cellular balance dictates heparan sulfate biosynthesis and shapes gastric cancer cell motility and invasion

Cited by 7 publications

References 76 publications

Molecular mechanism of decision-making in glycosaminoglycan biosynthesis

Molecular mechanism of decision-making in glycosaminoglycan biosynthesis

A biological guide to glycosaminoglycans: current perspectives and pending questions

Hippo cell signaling and HS-proteoglycans regulate tissue form and function, age-dependent maturation, extracellular matrix remodeling, and repair

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