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Integrin α3β1 regulates kidney collecting duct development via TRAF6-dependent K63-linked polyubiquitination of Akt.
Yazlovitskaya EM, Tseng HY, Viquez O, Tu T, Mernaugh G, McKee KK, Riggins K, Quaranta V, Pathak A, Carter BD, Yurchenco P, Sonnenberg A, Böttcher RT, Pozzi A, Zent R
(2015) Mol Biol Cell 26: 1857-74
MeSH Terms: Animals, Integrin alpha3beta1, Kidney Tubules, Collecting, Mice, Mice, Knockout, Morphogenesis, Proto-Oncogene Proteins c-akt, Signal Transduction, TNF Receptor-Associated Factor 6, Ubiquitination
Show Abstract · Added February 4, 2016
The collecting system of the kidney develops from the ureteric bud (UB), which undergoes branching morphogenesis, a process regulated by multiple factors, including integrin-extracellular matrix interactions. The laminin (LM)-binding integrin α3β1 is crucial for this developmental program; however, the LM types and LM/integrin α3β1-dependent signaling pathways are poorly defined. We show that α3 chain-containing LMs promote normal UB branching morphogenesis and that LM-332 is a better substrate than LM-511 for stimulating integrin α3β1-dependent collecting duct cell functions. We demonstrate that integrin α3β1-mediated cell adhesion to LM-332 modulates Akt activation in the developing collecting system and that Akt activation is PI3K independent but requires decreased PTEN activity and K63-linked polyubiquitination. We identified the ubiquitin-modifying enzyme TRAF6 as an interactor with the integrin β1 subunit and regulator of integrin α3β1-dependent Akt activation. Finally, we established that the developmental defects of TRAF6- and integrin α3-null mouse kidneys are similar. Thus K63-linked polyubiquitination plays a previously unrecognized role in integrin α3β1-dependent cell signaling required for UB development and may represent a novel mechanism whereby integrins regulate signaling pathways.
© 2015 Yazlovitskaya et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0).
1 Communities
4 Members
0 Resources
10 MeSH Terms
Integrin-free tetraspanin CD151 can inhibit tumor cell motility upon clustering and is a clinical indicator of prostate cancer progression.
Palmer TD, Martínez CH, Vasquez C, Hebron KE, Jones-Paris C, Arnold SA, Chan SM, Chalasani V, Gomez-Lemus JA, Williams AK, Chin JL, Giannico GA, Ketova T, Lewis JD, Zijlstra A
(2014) Cancer Res 74: 173-87
MeSH Terms: Animals, Cell Communication, Cell Line, Tumor, Cell Movement, Chick Embryo, Cohort Studies, Disease Progression, Humans, Immunohistochemistry, Integrin alpha3, Male, Mice, NIH 3T3 Cells, Platelet Aggregation, Prostatic Neoplasms, Protein Binding, Protein Structure, Tertiary, RNA, Messenger, Retrospective Studies, Tetraspanin 24, Tetraspanins
Show Abstract · Added December 30, 2013
Normal physiology relies on the organization of transmembrane proteins by molecular scaffolds, such as tetraspanins. Oncogenesis frequently involves changes in their organization or expression. The tetraspanin CD151 is thought to contribute to cancer progression through direct interaction with the laminin-binding integrins α3β1 and α6β1. However, this interaction cannot explain the ability of CD151 to control migration in the absence of these integrins or on non-laminin substrates. We demonstrate that CD151 can regulate tumor cell migration without direct integrin binding and that integrin-free CD151 (CD151(free)) correlates clinically with tumor progression and metastasis. Clustering CD151(free) through its integrin-binding domain promotes accumulation in areas of cell-cell contact, leading to enhanced adhesion and inhibition of tumor cell motility in vitro and in vivo. CD151(free) clustering is a strong regulator of motility even in the absence of α3 expression but requires PKCα, suggesting that CD151 can control migration independent of its integrin associations. The histologic detection of CD151(free) in prostate cancer correlates with poor patient outcome. When CD151(free) is present, patients are more likely to recur after radical prostatectomy and progression to metastatic disease is accelerated. Multivariable analysis identifies CD151(free) as an independent predictor of survival. Moreover, the detection of CD151(free) can stratify survival among patients with elevated prostate-specific antigen levels. Cumulatively, these studies demonstrate that a subpopulation of CD151 exists on the surface of tumor cells that can regulate migration independent of its integrin partner. The clinical correlation of CD151(free) with prostate cancer progression suggests that it may contribute to the disease and predict cancer progression.
1 Communities
2 Members
0 Resources
21 MeSH Terms
Integrin β1 is critical for gastrin-releasing peptide receptor-mediated neuroblastoma cell migration and invasion.
Lee S, Qiao J, Paul P, Chung DH
(2013) Surgery 154: 369-75
MeSH Terms: Cell Line, Tumor, Cell Movement, Gastrin-Releasing Peptide, Humans, Integrin alpha2, Integrin alpha3, Integrin beta1, Neoplasm Invasiveness, Neuroblastoma, Receptors, Bombesin
Show Abstract · Added March 7, 2014
BACKGROUND - Gastrin-releasing peptide (GRP) and its receptor, GRP-R, are critically involved in neuroblastoma tumorigenesis; however, the molecular mechanisms and signaling pathways that are responsible for GRP/GRP-R-induced cell migration and invasion remain unclear. In this study, we sought to determine the cell signals involved in GRP/GRP-R-mediated neuroblastoma cell migration and invasion.
METHODS - Human neuroblastoma cell lines SK-N-SH, LAN-1, and IMR-32 were used for our study. Transwell migration and invasion assays were performed after GRP (10(-7) M) stimulation. The cDNA GEArray Microarray kit was used to determine GRP-R-induced gene expression changes. Protein and membrane expression of integrin subunits were confirmed by Western blotting and flow cytometry analysis. siRNA transfection was performed using Lipofectamine 2000. For scratch assay, a confluent monolayer of cells in 6-well plates were wounded with micropipette tip and observed microscopically at 24 to 72 h.
RESULTS - GRP increased neuroblastoma cell migration and expressions of MMP-2 whereas the TIMP-1 level decreased. GRP-R overexpression stimulated SK-N-SH cell migration and upregulated integrin α2, α3, and β1 protein as well as mRNA expression. Targeted silencing of integrin β1 inhibited cell migration.
CONCLUSION - GRP/GRP-R signaling contributes to neuroblastoma cell migration and invasion. Moreover, the integrin ß1 subunit critically regulates GRP-R-mediated neuroblastoma cell migration and invasion.
Copyright © 2013 Mosby, Inc. All rights reserved.
0 Communities
1 Members
0 Resources
10 MeSH Terms
Upregulated expression of integrin α1 in mesangial cells and integrin α3 and vimentin in podocytes of Col4a3-null (Alport) mice.
Steenhard BM, Vanacore R, Friedman D, Zelenchuk A, Stroganova L, Isom K, St John PL, Hudson BG, Abrahamson DR
(2012) PLoS One 7: e50745
MeSH Terms: Animals, Autoantigens, Collagen Type IV, Disease Models, Animal, Glomerular Basement Membrane, Integrin alpha1, Integrin alpha3, Mesangial Cells, Mice, Mice, Knockout, Nephritis, Hereditary, Podocytes, Up-Regulation, Vimentin
Show Abstract · Added August 21, 2013
Alport disease in humans, which usually results in proteinuria and kidney failure, is caused by mutations to the COL4A3, COL4A4, or COL4A5 genes, and absence of collagen α3α4α5(IV) networks found in mature kidney glomerular basement membrane (GBM). The Alport mouse harbors a deletion of the Col4a3 gene, which also results in the lack of GBM collagen α3α4α5(IV). This animal model shares many features with human Alport patients, including the retention of collagen α1α2α1(IV) in GBMs, effacement of podocyte foot processes, gradual loss of glomerular barrier properties, and progression to renal failure. To learn more about the pathogenesis of Alport disease, we undertook a discovery proteomics approach to identify proteins that were differentially expressed in glomeruli purified from Alport and wild-type mouse kidneys. Pairs of cy3- and cy5-labeled extracts from 5-week old Alport and wild-type glomeruli, respectively, underwent 2-dimensional difference gel electrophoresis. Differentially expressed proteins were digested with trypsin and prepared for mass spectrometry, peptide ion mapping/fingerprinting, and protein identification through database searching. The intermediate filament protein, vimentin, was upregulated ∼2.5 fold in Alport glomeruli compared to wild-type. Upregulation was confirmed by quantitative real time RT-PCR of isolated Alport glomeruli (5.4 fold over wild-type), and quantitative confocal immunofluorescence microscopy localized over-expressed vimentin specifically to Alport podocytes. We next hypothesized that increases in vimentin abundance might affect the basement membrane protein receptors, integrins, and screened Alport and wild-type glomeruli for expression of integrins likely to be the main receptors for GBM type IV collagen and laminin. Quantitative immunofluorescence showed an increase in integrin α1 expression in Alport mesangial cells and an increase in integrin α3 in Alport podocytes. We conclude that overexpression of mesangial integrin α1 and podocyte vimentin and integrin α3 may be important features of glomerular Alport disease, possibly affecting cell-signaling, cell shape and cellular adhesion to the GBM.
1 Communities
2 Members
0 Resources
14 MeSH Terms
The role of a recombinant fragment of laminin-332 in integrin alpha3beta1-dependent cell binding, spreading and migration.
Yamashita H, Tripathi M, Harris MP, Liu S, Weidow B, Zent R, Quaranta V
(2010) Biomaterials 31: 5110-21
MeSH Terms: Cell Adhesion, Cell Adhesion Molecules, Cell Line, Cell Movement, Dose-Response Relationship, Drug, Humans, Integrin alpha3beta1, Protein Engineering, Recombinant Proteins
Show Abstract · Added December 10, 2013
The extracellular matrix (ECM) is thought to be an essential component of tissue scaffolding and engineering because it fulfills fundamental functions related to cell adhesion, migration, and three-dimensional organization. Natural ECM preparations, however, are challenging to work with because they are comprised of macromolecules that are large and insoluble in their functional state. Functional fragments of ECM macromolecules are a viable answer to this challenge, as demonstrated by the RGD-based engineered scaffolds, where the tri-peptide, Arg-Gly-Asp (RGD), represents the minimal functional unit of fibronectin and related ECM. Laminins (Ln) are main components of epithelial tissues, since they enter into the composition of basement membranes. Application of Ln to epithelial tissue engineering would be desirable, since they could help mimic ideal functional conditions for both lining and glandular epithelial tissues. However, functional fragments of Ln that could be used in artificial settings have not been characterized in detail. In this paper, we describe the production and application of the recombinant LG4 (rLG4) fragment of laminin-332 (Ln-332), and show that it mimics three fundamental functional properties of Ln-332: integrin-mediated cell adhesion, spreading, and migration. Adhesive structures formed by cells on rLG4 closely resemble those formed on Ln-332, as judged by microscopy-based analyses of their molecular composition. As on Ln-332, focal adhesion kinase (FAK) is phosphorylated in cells adhering to rLG4, and colocalized with other focal adhesion components. We conclude that rLG4 could be a useful substitute to recapitulate, in vitro, the tissue scaffolding properties of Ln-332.
Copyright 2010 Elsevier Ltd. All rights reserved.
3 Communities
2 Members
0 Resources
9 MeSH Terms
Laminin-332-beta1 integrin interactions negatively regulate invadopodia.
Liu S, Yamashita H, Weidow B, Weaver AM, Quaranta V
(2010) J Cell Physiol 223: 134-42
MeSH Terms: Animals, Carcinoma, Cell Adhesion, Cell Adhesion Molecules, Cell Line, Tumor, Cell Movement, Collagen Type I, Focal Adhesion Protein-Tyrosine Kinases, Integrin alpha3beta1, Integrin beta1, Neoplasm Invasiveness, Protein Kinase Inhibitors, Pseudopodia, RNA Interference, Rats, Transfection, Urinary Bladder Neoplasms, src-Family Kinases
Show Abstract · Added February 18, 2013
Adhesion of epithelial cells to basement membranes (BM) occurs through two major structures: actin-associated focal contacts and keratin-associated hemidesmosomes, both of which form on laminin-332 (Ln-332). In epithelial-derived cancer cells, additional actin-linked structures with putative adhesive properties, invadopodia, are frequently present and mediate BM degradation. A recent study proposed that BM invasion requires a proper combination of focal contacts and invadopodia for invading cells to gain traction through degraded BM, and suggested that these structures may compete for common molecular components such as Src kinase. In this study, we tested the role of the Ln-332 in regulating invadopodia in 804G rat bladder carcinoma cells, a cell line that secretes Ln-332 and forms all three types of adhesions. Expression of shRNA to Ln-332 gamma2 chain (gamma2-kd) led to increased numbers of invadopodia and enhanced extracellular matrix degradation. Replating gamma2-kd cells on Ln-332 or collagen-I fully recovered cell spreading and inhibition of invadopodia. Inhibition of alpha3 or beta1, but not alpha6 or beta4, phenocopied the effect of gamma2-kd, suggesting that alpha3beta1-mediated focal contacts, rather than alpha6beta4-mediated hemidesmosome pathways, intersect with invadopodia regulation. gamma2-kd cells exhibited alterations in focal contact-type structures and in activation of focal adhesion kinase (FAK) and Src kinase. Inhibition of FAK also increased invadopodia number, which was reversible with Src inhibition. These data are consistent with a model whereby actin-based adhesions can limit the availability of active Src that is capable of invadopodia initiation and identifies Ln-332-beta1 interactions as a potent upstream regulator that limits cell invasion.
J. Cell. Physiol. 223: 134-142, 2010. (c) 2009 Wiley-Liss, Inc.
3 Communities
2 Members
0 Resources
18 MeSH Terms
Dissection of the osteogenic effects of laminin-332 utilizing specific LG domains: LG3 induces osteogenic differentiation, but not mineralization.
Klees RF, Salasznyk RM, Ward DF, Crone DE, Williams WA, Harris MP, Boskey A, Quaranta V, Plopper GE
(2008) Exp Cell Res 314: 763-73
MeSH Terms: Calcification, Physiologic, Cell Adhesion, Cell Adhesion Molecules, Cell Differentiation, Cells, Cultured, Core Binding Factor Alpha 1 Subunit, Extracellular Signal-Regulated MAP Kinases, Focal Adhesion Protein-Tyrosine Kinases, Humans, Integrin alpha3beta1, Mesenchymal Stem Cells, Osteoblasts, Peptides, Protein Structure, Tertiary, Sp7 Transcription Factor, Transcription Factors
Show Abstract · Added February 18, 2013
The overall mechanisms governing the role of laminins during osteogenic differentiation of human mesenchymal stem cells (hMSC) are poorly understood. We previously reported that laminin-332 induces an osteogenic phenotype in hMSC and does so through a focal adhesion kinase (FAK) and extracellular signal-related kinase (ERK) dependent pathway. We hypothesized that this is a result of integrin-ECM binding, and that it occurs via the known alpha3 LG3 integrin binding domain of laminin-332. To test this hypothesis we cultured hMSC on several different globular domains of laminin-332. hMSC adhered best to the LG3 domain, and this adhesion maximally activated FAK and ERK within 120 min. Prolonged culturing (8 or 16 days) of hMSC on LG3 led to activation of the osteogenic transcription factor Runx2 and expression of key osteogenic markers (osterix, bone sialoprotein 2, osteocalcin, alkaline phosphatase, extracellular calcium) in hMSC. LG3 domain binding did not increase matrix mineralization, demonstrating that the LG3 domain alone is not sufficient to induce complete osteogenic differentiation in vitro. We conclude that the LG3 domain mediates attachment of hMSC to laminin-332 and that this adhesion recapitulates most, but not all, of the osteogenic differentiation associated with laminin-5 binding to hMSC.
2 Communities
1 Members
0 Resources
16 MeSH Terms
Integrin alpha3beta1, a novel receptor for alpha3(IV) noncollagenous domain and a trans-dominant Inhibitor for integrin alphavbeta3.
Borza CM, Pozzi A, Borza DB, Pedchenko V, Hellmark T, Hudson BG, Zent R
(2006) J Biol Chem 281: 20932-9
MeSH Terms: Cell Adhesion, Cell Line, Tumor, Cell Proliferation, Cells, Cultured, Endothelium, Vascular, Gene Expression Regulation, Neoplastic, Humans, Integrin alpha3beta1, Integrin alphaVbeta3, Integrins, Neovascularization, Pathologic, Protein Structure, Tertiary, Recombinant Proteins
Show Abstract · Added February 24, 2014
Exogenous soluble human alpha3 noncollagenous (NC1) domain of collagen IV inhibits angiogenesis and tumor growth. These biological functions are attributed to the binding of alpha3NC1 to integrin alphavbeta3. However, in some tumor cells that express integrin alphavbeta3, the alpha3NC1 domain does not inhibit proliferation, suggesting that integrin alphavbeta3 expression is not sufficient to mediate the anti-tumorigenic activity of this domain. Therefore, in the present study, we searched for novel binding receptors for the soluble alpha3NC1 domain in cells lacking alphavbeta3 integrin. In these cells, soluble alpha3NC1 bound integrin alpha3beta1; however, unlike alphavbeta3, alpha3beta1 integrin did not mediate cell adhesion to immobilized alpha3NC1 domain. Interestingly, in cells lacking integrin alpha3beta1, adhesion to the alpha3NC1 domain was enhanced due to activation of integrin alphavbeta3. These findings indicate that integrin alpha3beta1 is a receptor for the alpha3NC1 domain and transdominantly inhibits integrin alphavbeta3 activation. Thus integrin alpha3beta1, in conjunction with integrin alphavbeta3, modulates cellular responses to the alpha3NC1 domain, which may be pivotal in the mechanism underpinning its anti-angiogenic and anti-tumorigenic activities.
1 Communities
6 Members
0 Resources
13 MeSH Terms
The molecular basis of Goodpasture and Alport syndromes: beacons for the discovery of the collagen IV family.
Hudson BG
(2004) J Am Soc Nephrol 15: 2514-27
MeSH Terms: Amino Acid Sequence, Animals, Anti-Glomerular Basement Membrane Disease, Collagen Type IV, Female, Humans, Integrin alpha1, Integrin alpha2, Integrin alpha3, Isoantibodies, Isoantigens, Male, Molecular Biology, Mutation, Nephritis, Hereditary, Prognosis, Promoter Regions, Genetic, Severity of Illness Index
Added December 10, 2013
1 Communities
1 Members
0 Resources
18 MeSH Terms
Differential expression of collagen- and laminin-binding integrins mediates ureteric bud and inner medullary collecting duct cell tubulogenesis.
Chen D, Roberts R, Pohl M, Nigam S, Kreidberg J, Wang Z, Heino J, Ivaska J, Coffa S, Harris RC, Pozzi A, Zent R
(2004) Am J Physiol Renal Physiol 287: F602-11
MeSH Terms: Animals, Cell Line, Transformed, Cell Movement, Collagen, Gene Expression Regulation, Developmental, Humans, Integrin alpha1beta1, Integrin alpha2beta1, Integrin alpha3beta1, Integrin alpha6beta1, Integrin alpha6beta4, Kidney Medulla, Kidney Tubules, Collecting, Laminin, Mice, Mice, Mutant Strains, Ureter
Show Abstract · Added February 24, 2014
Inner medullary collecting ducts (IMCD) are terminally differentiated structures derived from the ureteric bud (UB). UB development is mediated by changes in the temporal and spatial expression of integrins and their respective ligands. We demonstrate both in vivo and in vitro that the UB expresses predominantly laminin receptors (alpha3beta1-, alpha6beta1-, and alpha6beta(4-integrins), whereas the IMCD expresses both collagen (alpha1beta1- and alpha2beta1-integrins) and laminin receptors. Cells derived from the IMCD, but not the UB, undergo tubulogenesis in collagen-I (CI) gels in an alpha1beta1- and alpha2beta1-dependent manner. UB cells transfected with the alpha2-integrin subunit undergo tubulogenesis in CI, suggesting that collagen receptors are required for branching morphogenesis in CI. In contrast, both UB and IMCD cells undergo tubulogenesis in CI/Matrigel gels. UB cells primarily utilize alpha3beta1- and alpha6-integrins, whereas IMCD cells mainly employ alpha1beta1 for this process. These results demonstrate a switch in integrin expression from primarily laminin receptors in the early UB to both collagen and laminin receptors in the mature IMCD, which has functional consequences for branching morphogenesis in three-dimensional cell culture models. This suggests that temporal and spatial changes in integrin expression could help organize the pattern of branching morphogenesis of the developing collecting system in vivo.
1 Communities
3 Members
0 Resources
17 MeSH Terms