Interaction with the Na,K-ATPase and Tissue Distribution of FXYD5 (Related to Ion Channel)

Lubarski, Irina; Pihakaski-Maunsbach, Kaarina; Karlish, Steven J. D.; Maunsbach, Arvid B.; Garty, Haim

doi:10.1074/jbc.m506397200

Cited by 94 publications

(144 citation statements)

References 36 publications

(36 reference statements)

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“…It is located at chromosome 19 and has a single transmembrane domain. It interacts with and modulates the properties of the Na þ , K þ ATPase (Ino et al, 2002;Lubarski et al, 2005). In human tissues increased dysadherin expression has been correlated with the development of metastasis and poor prognosis in gastric, pancreatic, colorectal, oesophageal, thyroid, tongue and cervical carcinomas, as well as in malignant melanoma (Aoki et al, 2003;Sato et al, 2003;Shimamura et al, 2003Shimamura et al, , 2004Nakanishi et al, 2004;Shimada et al, 2004a, b;Wu et al, 2004;Batistatou et al, 2005Batistatou et al, , 2006Nishizawa et al, 2005;Kyzas et al, 2006).…”

Section: Dysadherin In Breast Carcinomamentioning

confidence: 99%

In breast carcinoma dysadherin expression is correlated with invasiveness but not with E-cadherin

et al. 2007

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Reduction/loss of E-cadherin is associated with the development and progression of many epithelial tumours. Dysadherin, recently characterised by members of our research team, has an anti-cell -cell adhesion function and downregulates E-cadherin in a posttranscriptional manner. The aim of the present study was to study the role of dysadherin in breast cancer progression, in association with the E-cadherin expression and the histological type. We have selected ductal carcinoma, which is by far the most common type and lobular carcinoma, which has a distinctive microscopic appearance. Dysadherin and E-cadherin expression was examined immunohistochemically in 70 invasive ductal carcinomas, no special type (NST), and 30 invasive lobular carcinomas, with their adjacent in situ components. In ductal as well as in lobular carcinoma dysadherin was expressed only in the invasive and not in the in situ component, and this expression was independent of the E-cadherin expression. Specifically, all 10 (100%) Grade 1, 37out of 45(82.2%) Grade 2 and six out of 15 (40%) Grade 3 invasive ductal carcinomas showed preserved E-cadherin expression, while 'positive dysadherin expression' was found in six out of 10 (60%) Grade 1, 34 out of 45(75.5%) Grade 2 and all 15 (100%) Grade 3 neoplasms. None of the 30 infiltrating lobular carcinomas showed preserved E-cadherin expression, while all the 30 infiltrating lobular carcinomas exhibited 'positive dysadherin expression'. Dysadherin may play an important role in breast cancer progression by promoting invasion and, particularly in lobular carcinomas, it might also be used as a marker of invasion. Recent advances into molecular pathology of breast cancer have refined diagnostic accuracy and classification systems of the most common malignant neoplasm of women, rendering personalised therapy more possible. Today, there is a plethora of molecular genetic data that indicate differences in pathogenesis between the various types of breast carcinomas and thus support their categorisation, to the patient benefit. The demonstration of lack of E-cadherin expression in lobular neoplasms has had a sound impact with practical applications (Mastracci et al, 2005) In about half of lobular carcinomas, loss of E-cadherin involves genetic changes, that is loss of heterozygosity (LOH) at 16q22.1, while in the other half epigenetic events are involved (Knudsen and Wheelock, 2005;Mastracci et al, 2005). Ductal carcinomas, on the other hand, express E-cadherin, albeit in reduced levels and/or in abnormal cellular locations (Knudsen and Wheelock, 2005). Reduction/loss of E-cadherin has been associated with the development and progression of many epithelial neoplasms. Aberrant E-cadherin expression (heterogeneous, cytoplasmic, or absent) has been detected immunohistochemically in several cancers, including head and neck carcinoma, gastric adenocarcinoma, lobular breast carcinoma, lung cancer, colorectal carcinoma, prostate adenocarcinoma, pancreatic, and bladder cancer (Becker et

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Section: Dysadherin In Breast Carcinomamentioning

confidence: 99%

In breast carcinoma dysadherin expression is correlated with invasiveness but not with E-cadherin

et al. 2007

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“…A related effect has also been observed in renal cell carcinoma cells (7). CCL2 (also termed MCP-1 2 for monocyte chemotactic protein-1) is a small cytokine belonging to the CC chemokine family. It participates in monocyte recruitment during infection or under other inflammatory conditions (13).…”

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confidence: 93%

“…In our previous publication (2), we have shown that FXYD5 can be found in normal cells and that it is particularly abundant in epithelial cells in kidney, intestine, and lung. These epithelia are directly exposed to different levels of bacterial pathogens, present as contaminants in food or in airborne particles.…”

Section: Fxyd5 Effect On Ccl2 Secretion Is Not Exclusive To M1mentioning

confidence: 99%

“…The primary model system used in this study was the kidney collecting duct cell line M1, as FXYD5 is expressed in these ducts under normal conditions (2). In non-stimulated cells, CCL2 expression and secretion cannot be detected, either in cells containing or lacking FXYD5.…”

Section: Fxyd5 and Inflammationmentioning

confidence: 99%

“…FXYD5 (also termed dysadherin or RIC) is a structurally and functionally unique member of the FXYD family. As other FXYD proteins, FXYD5 specifically interacts with the Na,K-ATPase and alters its kinetics by increasing V max (2,3). However, in addition to regulating Na,K-ATPase kinetics, FXYD5 appears to have other functions.…”

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confidence: 99%

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FXYD5 Protein Has a Pro-inflammatory Role in Epithelial Cells

Lubarski-Gotliv

Asher

Dada

et al. 2016

Journal of Biological Chemistry

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The FXYD proteins are a family of small membrane proteins that share an invariant four amino acid signature motif F-X-Y-D and act as tissue-specific regulatory subunits of the Na,KATPase. FXYD5 (also termed dysadherin or RIC) is a structurally and functionally unique member of the FXYD family. As other FXYD proteins, FXYD5 specifically interacts with the Na,K-ATPase and alters its kinetics by increasing V max . However, unlike other family members FXYD5 appears to have additional functions, which cannot be readily explained by modulation of transport kinetics. Knockdown of FXYD5 in MDA-MB-231 breast cancer cells largely decreases expression and secretion of the chemokine CCL2 (MCP-1). A related effect has also been observed in renal cell carcinoma cells. The current study aims to further characterize the relationship between the expression of FXYD5 and CCL2 secretion. We demonstrate that transfection of M1 epithelial cell line with FXYD5 largely increases lipopolysaccharide (LPS) stimulated CCL2 mRNA and secretion of the translated protein. We have completed a detailed analysis of the molecular events leading to the above response. Our key findings indicate that FXYD5 generates a late response by increasing the surface expression of the TNF␣ receptor, without affecting its total protein level, or mRNA transcription. LPS administration to mice demonstrates induced secretion of CCL2 and TNF␣ in FXYD5-expressing lung peripheral tissue, which suggests a possible role for FXYD5 in normal epithelia during inflammation.FXYD is a family of type I plasma membrane proteins characterized by the extracellular motif Phe-Xxx-Tyr-Asp. All seven mammalian members of this family specifically interact with the Na,K-ATPase and they have been described to act as tissue specific regulators or auxiliary subunits of the Na,KATPase whose role is to adjust the pump's activity to the cell environment (1). FXYD5 (also termed dysadherin or RIC) is a structurally and functionally unique member of the FXYD family. As other FXYD proteins, FXYD5 specifically interacts with the Na,K-ATPase and alters its kinetics by increasing V max (2, 3). However, in addition to regulating Na,K-ATPase kinetics, FXYD5 appears to have other functions. FXYD5 has been identified as a cancer-associated protein whose expression inhibits E-cadherin and promotes metastasis (4). Clinical studies have demonstrated correlations between the abundance of FXYD5 and the progression of malignancies and survival chances of patients with various human cancers (for review see Ref. 5). Silencing FXYD5 decreases individual and collective cell motility, while its overexpression has the opposite effect (6 -8). In addition, the expression of FXYD5 has been associated with changes in cytoskeletal organization, altered cell shape and impairment of tight and adherence junctions (6 -10). The above observations are consistent with the fact that the extracellular domain of FXYD5 is much longer than that of other FXYD proteins and presumably undergoes excessive O-glycosylation (4, 11).Prev...

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