Trimeric Tn Antigen on Syndecan 1 Produced by ppGalNAc-T13 Enhances Cancer Metastasis via a Complex Formation with Integrin α5β1 and Matrix Metalloproteinase 9

Matsumoto, Yasuyuki; Zhang, Qing; Akita, Kaoru; Nakada, Hiroshi; Hamamura, Kazunori; Tsuchida, Akiko; Okajima, Tetsuya; Furukawa, Koichi; Urano, Takeshi

doi:10.1074/jbc.m113.455006

Cited by 29 publications

(26 citation statements)

References 40 publications

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“…In addition, syndecan-1 can act as regulator of a v b 3 and a v b 5 integrin activation [15,17]. Modulation of a 5 b 1 integrins by syndecan-1 was also reported during focal adhesion formation and migration [18][19][20]. Interestingly, the latter pathway can either enhance or suppress these processes [18][19][20].…”

Section: Introductionmentioning

confidence: 99%

“…Modulation of a 5 b 1 integrins by syndecan-1 was also reported during focal adhesion formation and migration [18][19][20]. Interestingly, the latter pathway can either enhance or suppress these processes [18][19][20]. Further, activation of focal adhesion kinase (FAK) and Rho GTPase has been implicated in syndecan-1-mediated effects on cell migration [16,21].…”

Section: Introductionmentioning

confidence: 99%

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A transmembrane C-terminal fragment of syndecan-1 is generated by the metalloproteinase ADAM17 and promotes lung epithelial tumor cell migration and lung metastasis formation

Pasqualon

Pruessmeyer

Weidenfeld

et al. 2015

Cell. Mol. Life Sci.

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Syndecan-1 is a heparan sulfate proteoglycan expressed by endothelial and epithelial cells and involved in wound healing and tumor growth. Surface-expressed syndecan-1 undergoes proteolytic shedding leading to the release of the soluble N-terminal ectodomain from a transmembrane C-terminal fragment (tCTF). We show that the disintegrin and metalloproteinase (ADAM) 17 generates a syndecan-1 tCTF, which can then undergo further intra-membrane proteolysis by γ-secretase. Scratch-induced wound closure of cultured lung epithelial A549 tumor cells associates with increased syndecan-1 cleavage as evidenced by the release of shed syndecan-1 ectodomain and enhanced generation of the tCTF. Both wound closure and the associated syndecan-1 shedding can be suppressed by inhibition of ADAM family proteases. Cell proliferation, migration and invasion into matrigel as well as several signaling pathways implicated in these responses are suppressed by silencing of syndecan-1. These defects of syndecan-1 deficient cells can be overcome by overexpression of syndecan-1 tCTF or a corresponding tCTF of syndecan-4 but not by overexpression of a tCTF lacking the transmembrane domain. Finally, lung metastasis formation of A549 cells in SCID mice was found to be dependent on syndecan-1, and the presence of syndecan-1 tCTF was sufficient for this activity. Thus, the syndecan-1 tCTF by itself is capable of mediating critical syndecan-1-dependent functions in cell proliferation, migration, invasion and metastasis formation and therefore can replace full length syndecan-1 in the situation of increased syndecan-1 shedding during cell migration and tumor formation.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A transmembrane C-terminal fragment of syndecan-1 is generated by the metalloproteinase ADAM17 and promotes lung epithelial tumor cell migration and lung metastasis formation

Pasqualon

Pruessmeyer

Weidenfeld

et al. 2015

Cell. Mol. Life Sci.

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“…However, Galnt13 was also identified as an up-regulated gene in high metastatic mouse lung cancer cell lines (Matsumoto et al 2012). In this case, the molecular basis of aggressive behavior was explained by GalNAc-T13 leading to formation of trimeric Tn antigen on syndecan-1 (Matsumoto et al 2013). Recently, high expression of GalNAc-T13 was also demonstrated in human lung cancer and this was correlated with poor prognosis, suggesting that this enzyme may represent a prognostic factor (Nogimori et al 2016).…”

Section: Introductionmentioning

confidence: 98%

“…However, it was previously reported that GalNAc-T13 differs in peptide substrate preferences from GalNAc-T1, and in particular with respect to important substrates such as Syndecan . We are interested in GalNAc-T13 because of its potential involvement in cancer biology (Berois et al 2006b;Matsumoto et al 2012;Matsumoto et al 2013;Nogimori et al 2016). Using microarray gene expression analysis in a metastatic xenograft-derived cell model of human neuroblastoma (so-called IGR-N-91), we found that GALNT13 was the most strongly up-regulated gene (12-fold) in metastatic malignant neuroblasts compared with primary tumor xenograft (Berois et al 2006b).…”

Section: Introductionmentioning

confidence: 99%

Revisiting the human polypeptide GalNAc-T1 and T13 paralogs

Festari

Trajtenberg²,

Berois

et al. 2016

Glycobiology

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Polypeptide GalNAc-transferases (GalNAc-Ts) constitute a family of 20 human glycosyltransferases (comprising 9 subfamilies), which initiate mucin-type O-glycosylation. The O-glycoproteome is thought to be differentially regulated via the different substrate specificities and expression patterns of each GalNAc-T isoforms. Here, we present a comprehensive in vitro analysis of the peptide substrate specificity of GalNAc-T13, showing that it essentially overlaps with the ubiquitous expressed GalNAc-T1 isoform found in the same subfamily as T13. We have also identified and partially characterized nine splice variants of GalNAc-T13, which add further complexity to the GalNAc-T family. Two variants with changes in their lectin domains were characterized by in vitro glycosylation assays, and one (Δ39Ex9) was inactive while the second one (Ex10b) had essentially unaltered activity. We used reverse transcription-polymerase chain reaction analysis of human neuroblastoma cell lines, normal brain and a small panel of neuroblastoma tumors to demonstrate that several splice variants (Ex10b, ΔEx9, ΔEx2-7 and ΔEx6/8-39bpEx9) were highly expressed in tumor cell lines compared with normal brain, although the functional implications remain to be unveiled. In summary, the GalNAc-T13 isoform is predicted to function similarly to GalNAc-T1 against peptide substrates in vivo, in contrast to a prior report, but is unique by being selectively expressed in the brain.

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“…In addition to the hypothesis above, it is also possible that there may exist some other proteins that mediate the functions of ppGalNAc-T13 in neurogenesis and that these proteins could be specifically glycosylated by ppGalNAc-T13. Besides PDPN, both sydecan-3 and syndecan-1 have been found to be the substrates of ppGalNAc-T13 (28,61,62), and sydecan-3 has been reportedly involved in axon guidance, neuralmigration,andneuronalplasticity (63,64).Meanwhile,O-glycosylation modifications have also been observed on several neuron-specific transmembrane or matrix proteins such as p75 (neurotrophin receptor), amyloid precursor protein, neural cell adhesion molecule, and testicans (65)(66)(67)(68), although little is known about their functions in neural development. Clearly, further study is needed to clarify the mechanisms of the distinct roles of ppGalNAc-T13 in neural differentiation.…”

Section: The Significance Of Ppgalnac-t13 and Pdpn In Neurogenesismentioning

confidence: 99%

Polypeptide N-Acetylgalactosaminyltransferase 13 Contributes to Neurogenesis via Stabilizing the Mucin-type O-Glycoprotein Podoplanin

Pang

et al. 2016

Journal of Biological Chemistry

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Mucin-type O-glycosylation is initiated by an evolutionarily conserved family of polypeptide N-acetylgalactosaminyltransferases (ppGalNAc-Ts). Previously, it was reported that ppGalNAc-T13 is restrictively expressed at a high level in the brain. Here we provide evidence for the critical role of ppGalNAc-T13 in neural differentiation. In detail, we show that the expression of ppGalNAc-T13 was dramatically up-regulated during early neurogenesis in mouse embryonic brains. Similar changes were also observed in cell models of neuronal differentiation by using either primary mouse cortical neural precursor cells or murine embryonal carcinoma P19 cells. Knockout of ppGalNAc-T13 in P19 cells suppressed not only neural induction but also neuronal differentiation. These effects are at least partly mediated by the mucin-type O-glycoprotein podoplanin (PDPN), as knockdown of PDPN led to a similar inhibition of neuronal differentiation and PDPN was significantly reduced at the posttranscriptional level after ppGalNAc-T13 knockout. Further data demonstrate that PDPN acts as a substrate of ppGalNAc-T13 and that the ppGalNAc-T13-mediated O-glycosylation on PDPN is important for its stability. Taken together, this study suggests that ppGalNAc-T13 contributes to neuronal differentiation through glycosylating and stabilizing PDPN, which provides insights into the regulatory roles of O-glycosylation in mammalian neural development.Development of the CNS involves a well ordered generation of a variety of distinct neural cell types with progressive restriction in fate potential of neural progenitors (1). This process is precisely regulated by a large set of transcriptional factors (2, 3) and occurs with the reorchestration of molecule expression on the cell surface. These molecules, as indicated by many previous reports, include not only various glycoproteins or glycolipids but also the glycans on them (4 -6). Accumulating evidence shows that cell surface glycans play crucial roles in CNS development, where they do not function independently but via regulating the functions of their carrier proteins or lipids. It has been reported that N-glycans modulate neural cell adhesion, axonal targeting, neural transmission, and neurite outgrowth by affecting the folding or trafficking of certain carrier glycoproteins such as synaptic vesicle protein 2 (SV2) and ionotropic glutamate receptors (7). Also, genetic inactivation of ST8Sia II and ST8Sia IV sialyltransferases, which catalyze polysialic acid structures on neural cell adhesion molecule, leads to severe defects in neurite outgrowth, synaptic plasticity, etc. (7). In contrast to the increasing evidence for the significance of sialylation and N-glycosylation, there is very limited information regarding the mechanistic roles of O-glycosylation in neural development (8).Mucin type O-glycosylation is an evolutionarily conserved protein modification that plays important roles in protein processing, secretion, stability, and ligand binding (9, 10). In mammals, it is initiated by a family of 20 ...

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Trimeric Tn Antigen on Syndecan 1 Produced by ppGalNAc-T13 Enhances Cancer Metastasis via a Complex Formation with Integrin α5β1 and Matrix Metalloproteinase 9

Cited by 29 publications

References 40 publications

A transmembrane C-terminal fragment of syndecan-1 is generated by the metalloproteinase ADAM17 and promotes lung epithelial tumor cell migration and lung metastasis formation

A transmembrane C-terminal fragment of syndecan-1 is generated by the metalloproteinase ADAM17 and promotes lung epithelial tumor cell migration and lung metastasis formation

Revisiting the human polypeptide GalNAc-T1 and T13 paralogs

Polypeptide N-Acetylgalactosaminyltransferase 13 Contributes to Neurogenesis via Stabilizing the Mucin-type O-Glycoprotein Podoplanin

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