pp-GalNAc-T13 induces high metastatic potential of murine Lewis lung cancer by generating trimeric Tn antigen

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

doi:10.1016/j.bbrc.2012.01.086

Cited by 28 publications

(29 citation statements)

References 21 publications

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“…We also found that ppGalNAc-T13, which is a family member of ppGalNAc transferases, was up-regulated as a result of reduced GM1, leading to enhanced metastasis by formation of trimeric Tn (tTn) antigen (three consecutive GalNAc-substituted Ser/Thr) on Syndecan 1 (Sdc1) (7). However, the roles of trimeric Tn antigen on Sdc1 and mechanisms for tTn antigen in the enhancement of cancer metastasis remain to be investigated.…”

mentioning

confidence: 92%

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

Zhang

Akita

et al. 2013

Journal of Biological Chemistry

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Background: ppGalNAc-T13 is up-regulated in high metastatic murine lung cancer cell lines. Results: Trimeric Tn on Syndecan 1 forms a complex with integrin ␣5␤1 and MMP-9, leading to cell adhesion and cancer metastasis. Conclusion: Reduction of GM1 induces ppGalNAc-T13 expression, and its product trimeric Tn enhances metastasis via integrins. Significance: A novel key molecule in cancer metastasis is identified.

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mentioning

confidence: 92%

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

Zhang

Akita

et al. 2013

Journal of Biological Chemistry

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“…This scenario resembles that of the GalNAc-T3 and T6 subfamily isoforms, where T3 is widely expressed, while T6 is more restricted. Interestingly, in both these subfamilies, the isoforms with restricted expression (GalNAc-T6 and T13, respectively) have been found to be de novo expressed in cancer (Freire et al 2006;Berois et al 2006a;Wandall et al 2007b;Gomes et al 2009;Li et al 2011;Matsumoto et al 2012), suggesting they may serve yet unknown important functions related to cancer biology.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, we found that GALNT13 expression in bone marrow is a strong predictor of poor clinical outcome in neuroblastoma patients (Berois et al 2006b). 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).…”

Section: Introductionmentioning

confidence: 95%

“…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%

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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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pp-GalNAc-T13 induces high metastatic potential of murine Lewis lung cancer by generating trimeric Tn antigen

Cited by 28 publications

References 21 publications

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

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

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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