URP1: a member of a novel family of PH and FERM domain-containing membrane-associated proteins is significantly over-expressed in lung and colon carcinomas

Weinstein, Edward J.; Bourner, Maureen; Head, Richard D.; Zakeri, Hamideh; Bauer, C.; Mazzarella, Richard

doi:10.1016/s0925-4439(03)00035-8

Cited by 69 publications

(68 citation statements)

References 30 publications

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“…Furthermore, cell spreading is perturbed upon reduction of kindlerin protein. Taken together with the observation that kindlerin is overexpressed in colon and lung carcinomas (2), our data support a role for kindlerin in mammalian cell adhesion and suggest that kindlerin may mediate TGF-␤ signaling in tumor progression via contributions to integrin-dependent cellular functions.…”

supporting

confidence: 81%

“…ent with our findings on kindlerin and supports a general role for the Mig-2 family in cell adhesion. To date, no reports have described URP2 function; however, its high expression levels in spleen, thymus, and peripheral blood leukocytes suggest a role specific to the immune system (2). Future experiments will be needed to address the role of the enrichment of kindlerin at membrane ruffles and sites of cell-cell contact in altered adhesion, migration, and morphology of TGF-␤-treated cells.…”

Section: Discussionmentioning

confidence: 99%

“…Kindlerin (also known as URP1 for UNC-112 related protein 1 or kindlin) is a member of a newly recognized protein family, which also includes Mig-2 and URP2 (2,3). An apparent kindlerin orthologue, UNC-112, has been studied in Caenorhabditis elegans (20).…”

mentioning

confidence: 99%

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The Kindler Syndrome Protein Is Regulated by Transforming Growth Factor-β and Involved in Integrin-mediated Adhesion

Kloeker¹,

Major²,

Calderwood

et al. 2004

Journal of Biological Chemistry

147

157

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Transforming growth factor-␤1 (TGF-␤1Consistent with these biochemical findings, kindlerin is present at focal adhesions, sites of integrin-rich, membrane-substratum adhesion. Additionally, kindlerin is required for normal cell spreading. Taken together, these data suggest a role for kindlerin in mediating cell processes that depend on integrins.The survival of cancer patients with solid tumors decreases dramatically when tumors are invasive and have an increased likelihood of metastasizing to distal sites. The enhanced invasiveness of tumor cells is attributed to epithelial to mesenchymal transition (EMT), 1 (5-8) a normal biological process that is critical for wound healing and development. EMT is characterized by a change in cell shape from a polarized epithelial cell to a flattened fibroblast-like morphology, a decrease in cell-cell junctions concurrent with a decrease in E-cadherin expression, and an increase in cell motility (5, 6). Transforming growth factor-␤1 (TGF-␤) is a major contributor to tumor progression and metastasis (9 -11), and several studies have shown that TGF-␤ promotes tumor cell invasiveness by promoting EMT (9,(12)(13)(14)(15). Despite the key role established for TGF-␤ in stimulating EMT and tumor progression, the molecular mechanisms by which TGF-␤ promotes EMT have not been fully elucidated.Microarray analysis of a TGF-␤-responsive cell line, human mammary epithelial cells (HMEC), led us to identify kindlerin as a TGF-␤-inducible gene. Kindlerin is mutated in Kindler syndrome, a rare autosomal-recessive genodermatosis (1, 3). Early in life patients with Kindler syndrome endure blistering of the skin and photosensitivity, which progresses to diffuse poikiloderma followed by cutaneous atrophy (16, 17). The clinical presentation of this disease is similar to patients with junctional epidermolysis bullosa harboring mutations in ␣ 6 and ␤ 4 integrin genes (18,19).Kindlerin (also known as URP1 for UNC-112 related protein 1 or kindlin) is a member of a newly recognized protein family, which also includes Mig-2 and URP2 (2, 3). An apparent kindlerin orthologue, UNC-112, has been studied in Caenorhabditis elegans (20). The unc-112 gene is essential for embryogenesis, and it displays a genetic interaction with integrins (20). Because integrins play a critical role in mammalian cell adhesion and migration, we postulated that kindlerin may be involved in TGF-␤-stimulated EMT through interactions with integrins.Here we report that kindlerin expression is responsive to TGF-␤ levels, that kindlerin localizes in focal adhesions (integrin-rich signaling centers that integrate extracellular matrix attachment and cytoskeletal organization), and that kindlerin forms complexes with integrin ␤ subunit cytoplasmic domains. Furthermore, cell spreading is perturbed upon reduction of kindlerin protein. Taken together with the observation that kindlerin is overexpressed in colon and lung carcinomas (2), our data support a role for kindlerin in mammalian cell adhesion and suggest that kindlerin may mediate TGF...

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supporting

confidence: 81%

Section: Discussionmentioning

confidence: 99%

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The Kindler Syndrome Protein Is Regulated by Transforming Growth Factor-β and Involved in Integrin-mediated Adhesion

Kloeker¹,

Major²,

Calderwood

et al. 2004

Journal of Biological Chemistry

147

157

View full text Add to dashboard Cite

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“…The authors speculated that MIG2 is overexpressed on the transcriptional level, and that MIG2 could be involved in hormone-mediated growth. Weinstein and colleagues found that expression patterns for the three protein family members, MIG2, URP1, and URP2 differed among various tumor tissues (13). The authors reported that URP1 expression was increased in 70% of colon and 60% of lung carcinomas, but was not increased in breast carcinomas.…”

Section: Discussionmentioning

confidence: 99%

“…MIG2 belongs to a newly recognized protein family comprising URP1, URP2 and the Caenorhabditis elegans protein, UNC-112, which all share a unique protein structure consisting of two 4.1-ezrinradixin-moesin domains flanking a pleckstrin homology domain (13,14). MIG2 has been further characterized as a component of cell-ECM adhesion sites and described its involvement in controlling cell shape and spreading (15).…”

Section: Introductionmentioning

confidence: 99%

Use of an Aggressive MCF-7 Cell Line Variant, TMX2-28, to Study Cell Invasion in Breast Cancer

Gozgit

Pentecost

Marconi

et al. 2006

Molecular Cancer Research

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An estrogen receptor -negative variant of the MCF-7 breast cancer cell line, TMX2-28, was used as a model in which to study breast cancer cell invasion. Using a reconstituted basement membrane (Matrigel) assay to evaluate cell invasion, we determined that TMX2-28 cells are more invasive than MCF-7 cells and that the invasiveness of TMX2-28 is similar to that of the aggressive MDA-MB-231 breast cancer cell line. TMX2-28 cells displayed a rounded, epithelial cell -like morphology, suggesting an amoeboid mode of cell invasion, in contrast to the mesenchymal mode of invasion characteristic of spindle-shaped, fibroblast-like MDA-MB-231 cells. Using real-time reverse transcription-PCR, we found that mitogen-inducible gene 2 (MIG2) is expressed at a 17-fold higher level in TMX2-28 cells than in nonaggressive MCF-7 cells and that MIG2 mRNA levels are low in the nontumorigenic human mammary epithelial cell line, 184. We determined that MIG2 plays a role in cell invasion by using small interfering RNA (siRNA) to suppress the expression of MIG2 mRNA levels in TMX2-28 cells. TMX2-28 cell invasion was reduced by 48% when the cells were transfected with siRNAs targeting MIG2, relative to cells transfected with siRNAs against glyceraldehyde-3-phosphate dehydrogenase. Finally, MIG2 expression was evaluated in reductive mammoplasty and breast tumor tissue. Although all 21 normal tissues from reduction mammoplasty showed immunoreactivity for MIG2, ranging from weak (62%) to strong (24%), only half of the 34 formalin-fixed breast tumors showed immunoreactivity for MIG2. Of these 17 positive cases, 10 were considered to overexpress MIG2 (moderate to strong staining). Examination of 30 frozen breast tumors supported the finding that MIG2 is overexpressed in a subset of breast cancers. We suggest that MIG2's normal regulation and function are disrupted in breast cancer. (Mol Cancer Res 2006;4(12):905 -13)

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Associations of the Top 20 Alzheimer Disease Risk Variants With Brain Amyloidosis

et al. 2018

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IMPORTANCE Late-onset Alzheimer disease (AD) is highly heritable. Genome-wide association studies have identified more than 20 AD risk genes. The precise mechanism through which many of these genes are associated with AD remains unknown. OBJECTIVE To investigate the association of the top 20 AD risk variants with brain amyloidosis. DESIGN, SETTING, AND PARTICIPANTS This study analyzed the genetic and florbetapir F 18 data from 322 cognitively normal control individuals, 496 individuals with mild cognitive impairment, and 159 individuals with AD dementia who had genome-wide association studies and 18F-florbetapir positron emission tomographic data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI), a prospective, observational, multisite tertiary center clinical and biomarker study. This ongoing study began in 2005. MAIN OUTCOMES AND MEASURES The study tested the association of AD risk allele carrier status (exposure) with florbetapir mean standard uptake value ratio (outcome) using stepwise multivariable linear regression while controlling for age, sex, and apolipoprotein E ε4 genotype. The study also reports on an exploratory 3-dimensional stepwise regression model using an unbiased voxelwise approach in Statistical Parametric Mapping 8 with cluster and significance thresholds at 50 voxels and uncorrected P < .01. RESULTS This study included 977 participants (mean [SD] age, 74 [7.5] years; 535 [54.8%] male and 442 [45.2%] female) from the ADNI-1, ADNI-2, and ADNI–Grand Opportunity. The adenosine triphosphate–binding cassette subfamily A member 7 (ABCA7) gene had the strongest association with amyloid deposition (χ2 = 8.38, false discovery rate–corrected P < .001), after apolioprotein E ε4. Significant associations were found between ABCA7 in the asymptomatic and early symptomatic disease stages, suggesting an association with rapid amyloid accumulation. The fermitin family homolog 2 (FERMT2) gene had a stage-dependent association with brain amyloidosis (FERMT2 × diagnosis χ2 = 3.53, false discovery rate–corrected P = .05), which was most pronounced in the mild cognitive impairment stage. CONCLUSIONS AND RELEVANCE This study found an association of several AD risk variants with brain amyloidosis. The data also suggest that AD genes might differentially regulate AD pathologic findings across the disease stages.

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URP1: a member of a novel family of PH and FERM domain-containing membrane-associated proteins is significantly over-expressed in lung and colon carcinomas

Cited by 69 publications

References 30 publications

The Kindler Syndrome Protein Is Regulated by Transforming Growth Factor-β and Involved in Integrin-mediated Adhesion

The Kindler Syndrome Protein Is Regulated by Transforming Growth Factor-β and Involved in Integrin-mediated Adhesion

Use of an Aggressive MCF-7 Cell Line Variant, TMX2-28, to Study Cell Invasion in Breast Cancer

Associations of the Top 20 Alzheimer Disease Risk Variants With Brain Amyloidosis

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