Expression of pre-selected TMEMs with predicted ER localization as potential classifiers of ccRCC tumors

Wrzesiński, Tomasz; Szeląg, Małgorzata; Cieślikowski, Wojciech A; Ida, Agnieszka; Giles, Rachel; Zodro, E.; Szumska, Joanna; Poźniak, Joanna; Kwias, Zbigniew; Bluyssen, Hans A.R.; Wesoły, Joanna

doi:10.1186/s12885-015-1530-4

Cited by 91 publications

(85 citation statements)

References 81 publications

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“…This led to the identification of TMEM2 (HUGO Gene Nomenclature ID: 11869), a member of the TMEM family, as a candidate. The TMEM family is a heterogeneous collection of more than 300 different human open reading frames that are grouped based only on the presence of at least one putative transmembrane domain (18). The functions of many of TMEM proteins are unknown.…”

Section: Tmem2 Is Expressed On the Cell Surface With A Type II Membramentioning

confidence: 99%

A mammalian homolog of the zebrafish transmembrane protein 2 (TMEM2) is the long-sought-after cell-surface hyaluronidase

Yamamoto

Tobisawa

Inubushi

et al. 2017

Journal of Biological Chemistry

140

162

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Edited by Amanda J. Fosang Hyaluronan (HA) is an extremely large polysaccharide (glycosaminoglycan) involved in many cellular functions. HA catabolism is thought to involve the initial cleavage of extracellular high-molecular-weight (HMW) HA into intermediate-size HA by an extracellular or cell-surface hyaluronidase, internalization of intermediate-size HA, and complete degradation into monosaccharides in lysosomes. Despite considerable research, the identity of the hyaluronidase responsible for the initial HA cleavage in the extracellular space remains elusive. HYAL1 and HYAL2 have properties more consistent with lysosomal hyaluronidases, whereas CEMIP/KIAA1199, a recently identified HA-binding molecule that has HA-degrading activity, requires the participation of the clathrincoated pit pathway of live cells for HA degradation. Here we show that transmembrane protein 2 (TMEM2), a mammalian homolog of a protein playing a role in zebrafish endocardial cushion development, is a cell-surface hyaluronidase. Live immunostaining and surface biotinylation assays confirmed that mouse TMEM2 is expressed on the cell surface in a type II transmembrane topology. TMEM2 degraded HMW-HA into ϳ5-kDa fragments but did not cleave chondroitin sulfate or dermatan sulfate, indicating its specificity to HA. The hyaluronidase activity of TMEM2 was Ca 2؉ -dependent; the enzyme's pH optimum is around 6 -7, and unlike CEMIP/ KIAA1199, TMEM2 does not require the participation of live cells for its hyaluronidase activity. Moreover, TMEM2-expressing cells could eliminate HA immobilized on a glass surface in a contact-dependent manner. Together, these data suggest that TMEM2 is the long-sought-after hyaluronidase that cleaves extracellular HMW-HA into intermediate-size fragments before internalization and degradation in the lysosome.Hyaluronic acid (HA) 2 is a glycosaminoglycan composed of repeating disaccharide units of glucuronic acid and N-acetylglucosamine. It is a linear polymer of extremely large molecular mass, often exceeding 10 6 Da (1). The sheer size of HA suggests that cells should have very efficient mechanisms for its metabolism. In fact, one-third of the total body HA, which is estimated to be 15 g in a human with a 70-kg body weight, is thought to be turned over daily (2). In skin, the metabolic halflife of HA is 1 to 1.5 days (3). It is believed that high-molecularweight (HMW) HA (10 6 -10 7 Da) is first degraded extracellularly into intermediate-size fragments of 10 -100 kDa. These are then internalized and degraded to monosaccharides by the combined actions of lysosomal hyaluronidase and exoglucosidases (4). Considering the accumulating evidence for the role of HA degradation in tumor invasion and metastasis (5), identifying the molecule(s) that degrade HA on the cell surface is an important biological issue.The HYAL family molecules have been implicated as the major players in HA catabolism. HYAL1 and HYAL2 are expressed widely and postulated to be the key hyaluronidases involved in HA catabolism in somatic tissues. How...

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Section: Tmem2 Is Expressed On the Cell Surface With A Type II Membramentioning

confidence: 99%

A mammalian homolog of the zebrafish transmembrane protein 2 (TMEM2) is the long-sought-after cell-surface hyaluronidase

Yamamoto

Tobisawa

Inubushi

et al. 2017

Journal of Biological Chemistry

140

162

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“…Detailed characteristics for each patient are provided in Supplementary Table S1 and are summarized in Table . Methods used to collect material from patients and determine clinical characteristics have been described elsewhere …”

Section: Methodsmentioning

confidence: 99%

“…These methods have been described elsewhere . The list of PCR primers is provided in Supplementary Table S2.…”

Section: Methodsmentioning

confidence: 99%

Potential protective role of Grainyhead‐like genes in the development of clear cell renal cell carcinoma

Pawlak

Kikulska

Wrzesiński

et al. 2017

Molecular Carcinogenesis

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The involvement of Grainyhead-like (GRHL) transcription factors in various cancers is well documented. However, little is known about their role in clear cell renal cell carcinoma (ccRCC). We discovered that the expression of two of these factors-GRHL1 and GRHL2-are downregulated in ccRCC samples, and their expression is correlated with the expression of VHL gene. This suggests a functional link between the GRHL transcription factors and one of the best known tumor suppressors. Although the GRHL genes are not mutated in ccRCC, some of the single nucleotide polymorphisms in these genes may indicate an increased risk of ccRCC development and/or may allow to assess patients' prognoses and predict their responses to various forms of therapy. Silencing of GRHL2 expression in non-tumorigenic kidney cell line results in increased cell proliferation, increased resistance to apoptosis, as well as changes in the levels of selected proteins involved in the pathogenesis of ccRCC. These changes support the potential role for GRHL2 as a suppressor of ccRCC.

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“…Later, TMEM207 appeared to be also localized in the endoplasmic reticulum by bioinformatic analysis (36). TMEM207 expression is strictly regulated in human tissues and cells.…”

Section: Physiological Cellular and Tissue Expression And Biological mentioning

confidence: 99%

Cancerous Protein Network That Inhibits the Tumor Suppressor Function of WW Domain-Containing Oxidoreductase (WWOX) by Aberrantly Expressed Molecules

2018

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Recent findings indicate that the WW domain-containing oxidoreductase (WWOX) is a tumor suppressor protein that contains two N-terminal WW domains and a central short-chain dehydrogenase/reductase domain. WWOX protein mediates multiple signaling networks that suppress carcinogenesis through binding of its first WW domain to various cancer-associated proteins, i.e., p73, AP-2γ, and others. Although the tumor suppressor property of WWOX is inarguable, WWOX is not inactivated in the manner characteristic of the canonical Knudson hypothesis. Impairment of both alleles of WWOX is thought to be a rare event, only occurring in a few cancer cell lines. How is the tumor suppressor function of WWOX impaired in cancer cells? Recent advances highlight that a small transmembrane protein possessing a PPxY motif, called TMEM207, and its relatives are aberrantly expressed in various cancer cells and hinder the tumor suppressor function of WWOX through inhibiting its WW domain. Here, we review the recent findings related to the pathobiological properties of TMEM207 and its relatives based on clinicopathological and experimental pathological studies.

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Expression of pre-selected TMEMs with predicted ER localization as potential classifiers of ccRCC tumors

Cited by 91 publications

References 81 publications

A mammalian homolog of the zebrafish transmembrane protein 2 (TMEM2) is the long-sought-after cell-surface hyaluronidase

A mammalian homolog of the zebrafish transmembrane protein 2 (TMEM2) is the long-sought-after cell-surface hyaluronidase

Potential protective role of Grainyhead‐like genes in the development of clear cell renal cell carcinoma

Cancerous Protein Network That Inhibits the Tumor Suppressor Function of WW Domain-Containing Oxidoreductase (WWOX) by Aberrantly Expressed Molecules

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