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The collagen receptor discoidin domain receptor 2 stabilizes SNAIL1 to facilitate breast cancer metastasis.
Zhang K, Corsa CA, Ponik SM, Prior JL, Piwnica-Worms D, Eliceiri KW, Keely PJ, Longmore GD
(2013) Nat Cell Biol 15: 677-87
MeSH Terms: Animals, Breast Neoplasms, Cadherins, Carcinoma, Ductal, Breast, Cell Line, Tumor, Cell Movement, Cell Proliferation, Discoidin Domain Receptors, Epithelial-Mesenchymal Transition, Female, HEK293 Cells, Humans, Mice, Mice, Inbred BALB C, Mitogen-Activated Protein Kinase 1, Neoplasm Invasiveness, Neoplasm Metastasis, Phosphorylation, RNA Interference, RNA, Small Interfering, Receptor Protein-Tyrosine Kinases, Receptors, Collagen, Receptors, Mitogen, Signal Transduction, Snail Family Transcription Factors, Transcription Factors
Show Abstract · Added July 31, 2013
Increased stromal collagen deposition in human breast tumours correlates with metastases. We show that activation of the collagen I receptor DDR2 (discoidin domain receptor 2) regulates SNAIL1 stability by stimulating ERK2 activity, in a Src-dependent manner. Activated ERK2 directly phosphorylates SNAIL1, leading to SNAIL1 nuclear accumulation, reduced ubiquitylation and increased protein half-life. DDR2-mediated stabilization of SNAIL1 promotes breast cancer cell invasion and migration in vitro, and metastasis in vivo. DDR2 expression was observed in most human invasive ductal breast carcinomas studied, and was associated with nuclear SNAIL1 and absence of E-cadherin expression. We propose that DDR2 maintains SNAIL1 level and activity in tumour cells that have undergone epithelial-mesenchymal transition (EMT), thereby facilitating continued tumour cell invasion through collagen-I-rich extracellular matrices by sustaining the EMT phenotype. As such, DDR2 could be an RTK (receptor tyrosine kinase) target for the treatment of breast cancer metastasis.
1 Communities
0 Members
0 Resources
26 MeSH Terms
Inhibition of integrin α2β1 ameliorates glomerular injury.
Borza CM, Su Y, Chen X, Yu L, Mont S, Chetyrkin S, Voziyan P, Hudson BG, Billings PC, Jo H, Bennett JS, Degrado WF, Eckes B, Zent R, Pozzi A
(2012) J Am Soc Nephrol 23: 1027-38
MeSH Terms: Acute Kidney Injury, Albuminuria, Analysis of Variance, Animals, Blotting, Western, Disease Models, Animal, Doxorubicin, Enzyme-Linked Immunosorbent Assay, Flow Cytometry, Immunohistochemistry, Integrin alpha2beta1, Kidney Function Tests, Kidney Glomerulus, Male, Mesangial Cells, Mice, Mice, Inbred BALB C, Mice, Knockout, Random Allocation, Receptors, Collagen
Show Abstract · Added February 25, 2014
Mesangial cells and podocytes express integrins α1β1 and α2β1, which are the two major collagen receptors that regulate multiple cellular functions, including extracellular matrix homeostasis. Integrin α1β1 protects from glomerular injury by negatively regulating collagen production, but the role of integrin α2β1 in renal injury is unclear. Here, we subjected wild-type and integrin α2-null mice to injury with adriamycin or partial renal ablation. In both of these models, integrin α2-null mice developed significantly less proteinuria and glomerulosclerosis. In addition, selective pharmacological inhibition of integrin α2β1 significantly reduced adriamycin-induced proteinuria, glomerular injury, and collagen deposition in wild-type mice. This inhibitor significantly reduced collagen synthesis in wild-type, but not integrin α2-null, mesangial cells in vitro, demonstrating that its effects are integrin α2β1-dependent. Taken together, these results indicate that integrin α2β1 contributes to glomerular injury by positively regulating collagen synthesis and suggest that its inhibition may be a promising strategy to reduce glomerular injury and proteinuria.
1 Communities
7 Members
1 Resources
20 MeSH Terms
Suboptimal activation of protease-activated receptors enhances alpha2beta1 integrin-mediated platelet adhesion to collagen.
Marjoram RJ, Voss B, Pan Y, Dickeson SK, Zutter MM, Hamm HE, Santoro SA
(2009) J Biol Chem 284: 34640-7
MeSH Terms: Amino Acid Motifs, Animals, Blood Platelets, Carrier Proteins, Collagen, GTP-Binding Protein alpha Subunits, Gi-Go, Humans, Integrin alpha2beta1, Mice, Mice, Inbred C57BL, Peptides, Platelet Adhesiveness, Platelet Aggregation, Platelet Membrane Glycoproteins, Rats, Receptor, PAR-1, Receptors, Collagen, Receptors, G-Protein-Coupled, Receptors, IgG, Receptors, Thrombin, Signal Transduction, Thrombin, Type C Phospholipases
Show Abstract · Added December 10, 2013
Thrombin and fibrillar collagen are potent activators of platelets at sites of vascular injury. Both agonists cause platelet shape change, granule secretion, and aggregation to form the primary hemostatic plug. Human platelets express two thrombin receptors, protease-activated receptors 1 and 4 (PAR1 and PAR4) and two collagen receptors, the alpha(2)beta(1) integrin (alpha(2)beta(1)) and the glycoprotein VI (GPVI)/FcRgamma chain complex. Although these receptors and their signaling mechanisms have been intensely studied, it is not known whether and how these receptors cooperate in the hemostatic function of platelets. This study examined cooperation between the thrombin and collagen receptors in platelet adhesion by utilizing a collagen-related peptide (alpha2-CRP) containing the alpha(2)beta(1)-specific binding motif, GFOGER, in conjunction with PAR-activating peptides. We demonstrate that platelet adhesion to alpha2-CRP is substantially enhanced by suboptimal PAR activation (agonist concentrations that do not stimulate platelet aggregation) using the PAR4 agonist peptide and thrombin. The enhanced adhesion induced by suboptimal PAR4 activation was alpha(2)beta(1)-dependent and GPVI/FcRgamma-independent as revealed in experiments with alpha(2)beta(1)- or FcRgamma-deficient mouse platelets. We further show that suboptimal activation of other platelet G(q)-linked G protein-coupled receptors (GPCRs) produces enhanced platelet adhesion to alpha2-CRP. The enhanced alpha(2)beta(1)-mediated platelet adhesion is controlled by phospholipase C (PLC), but is not dependent on granule secretion, activation of alpha(IIb)beta(3) integrin, or on phosphoinositol-3 kinase (PI3K) activity. In conclusion, we demonstrate a platelet priming mechanism initiated by suboptimal activation of PAR4 or other platelet G(q)-linked GPCRs through a PLC-dependent signaling cascade that promotes enhanced alpha(2)beta(1) binding to collagens containing GFOGER sites.
1 Communities
2 Members
0 Resources
23 MeSH Terms
Integrin alpha1beta1 controls reactive oxygen species synthesis by negatively regulating epidermal growth factor receptor-mediated Rac activation.
Chen X, Abair TD, Ibanez MR, Su Y, Frey MR, Dise RS, Polk DB, Singh AB, Harris RC, Zent R, Pozzi A
(2007) Mol Cell Biol 27: 3313-26
MeSH Terms: Animals, Cell Membrane, Cell Shape, Cells, Cultured, Collagen, Down-Regulation, Enzyme Activation, ErbB Receptors, Humans, Integrin alpha1beta1, Ligands, Mesangial Cells, Mice, Mice, Knockout, Phosphorylation, Protein Binding, Proto-Oncogene Proteins c-vav, Reactive Oxygen Species, Receptors, Collagen, rac GTP-Binding Proteins
Show Abstract · Added February 24, 2014
Integrins control many cell functions, including generation of reactive oxygen species (ROS) and regulation of collagen synthesis. Mesangial cells, found in the glomerulus of the kidney, are able to produce large amounts of ROS via the NADPH oxidase. We previously demonstrated that integrin alpha1-null mice develop worse fibrosis than wild-type mice following glomerular injury and this is due, in part, to excessive ROS production by alpha1-null mesangial cells. In the present studies, we describe the mechanism whereby integrin alpha1-null mesangial cells produce excessive ROS. Integrin alpha1-null mesangial cells have constitutively increased basal levels of activated Rac1, which result in its increased translocation to the cell membrane, excessive ROS production, and consequent collagen IV deposition. Basal Rac1 activation is a direct consequence of ligand-independent increased epidermal growth factor receptor (EGFR) phosphorylation in alpha1-null mesangial cells. Thus, our study demonstrates that integrin alpha1beta1-EGFR cross talk is a key step in negatively regulating Rac1 activation, ROS production, and excessive collagen synthesis, which is a hallmark of diseases characterized by irreversible fibrosis.
1 Communities
4 Members
0 Resources
20 MeSH Terms
Mammary epithelial cell-cycle progression via the alpha(2)beta(1) integrin: unique and synergistic roles of the alpha(2) cytoplasmic domain.
Klekotka PA, Santoro SA, Ho A, Dowdy SF, Zutter MM
(2001) Am J Pathol 159: 983-92
MeSH Terms: Breast, CDC2-CDC28 Kinases, Cell Cycle, Collagen, Cyclin E, Cyclin-Dependent Kinase 2, Cyclin-Dependent Kinases, Cytoplasm, Drug Synergism, Epithelial Cells, Female, Humans, Integrins, Protein-Serine-Threonine Kinases, Receptor, Insulin, Receptors, Collagen, S Phase, Signal Transduction, Transfection
Show Abstract · Added February 16, 2014
The alpha(2)beta(1) integrin supports cell-cycle progression of mammary epithelial cells adherent to type I collagen matrices. Integrin collagen receptors containing the alpha(2) cytoplasmic domain stimulated expression of cyclin E and cyclin-dependent kinase (cdk)2, resulting in cyclin E/cdk2 activation in the absence of growth factors other than insulin. Integrin collagen receptors in which the alpha(2) cytoplasmic domain was replaced by the alpha(1) cytoplasmic domain or an alpha(2) subunit cytoplasmic domain truncated after the GFFKR sequence failed to stimulate cyclin E/cdk2 activation or entry into S phase in the absence of growth factors. Although overexpression of cyclins D or E or cdk2 in cells expressing the integrin collagen receptor with the alpha(1)-integrin cytoplasmic domain did not restore G(1) progression when mammary epithelial cells adhered to type I collagen, co-expression of cyclin E and cdk2 did rescue the ability of the transfectants to enter S phase. Activation of cyclin E/cdk2 complex by mammary epithelial cells required synergy between adhesion mediated by an integrin collagen receptor containing the alpha(2)-integrin subunit cytoplasmic domain and the insulin receptor.
1 Communities
2 Members
0 Resources
19 MeSH Terms
Pro-collagenase-1 (matrix metalloproteinase-1) binds the alpha(2)beta(1) integrin upon release from keratinocytes migrating on type I collagen.
Dumin JA, Dickeson SK, Stricker TP, Bhattacharyya-Pakrasi M, Roby JD, Santoro SA, Parks WC
(2001) J Biol Chem 276: 29368-74
MeSH Terms: Adult, Binding Sites, Blood Platelets, Cell Movement, Cells, Cultured, Collagen, Collagenases, Enzyme Precursors, Humans, In Situ Hybridization, Integrins, Keratinocytes, Matrix Metalloproteinase 1, Matrix Metalloproteinase 3, Matrix Metalloproteinase 7, Matrix Metalloproteinase 9, Platelet Adhesiveness, Receptors, Collagen, Skin, Transcription, Genetic, U937 Cells
Show Abstract · Added March 5, 2014
In injured skin, collagenase-1 (matrix metalloproteinase-1 (MMP-1)) is induced in migrating keratinocytes. This site-specific expression is regulated by binding of the alpha(2)beta(1) integrin with dermal type I collagen, and the catalytic activity of MMP-1 is required for keratinocyte migration. Because of this functional association among substrate/ligand, receptor, and proteinase, we assessed whether the integrin also directs the compartmentalization of MMP-1 to its matrix target. Indeed, pro-MMP-1 co-localized to sites of alpha(2)beta(1) contacts in migrating keratinocytes. Furthermore, pro-MMP-1 co-immunoprecipitated with alpha(2)beta(1) from keratinocytes, and alpha(2)beta(1) co-immunoprecipitated with pro-MMP-1. No other MMPs bound alpha(2)beta(1), and no other integrins interacted with MMP-1. Pro-MMP-1 also provided a substrate for alpha(2)beta(1)-dependent adhesion of platelets. Complex formation on keratinocytes was most efficient on native type I collagen and reduced or ablated on denatured or cleaved collagen. Competition studies suggested that the alpha(2) I domain interacts with the linker and hemopexin domains of pro-MMP-1, not with the pro-domain. These data indicate that the interaction of pro-MMP-1 with alpha(2)beta(1) confines this proteinase to points of cell contact with collagen and that the ternary complex of integrin, enzyme, and substrate function together to drive and regulate keratinocyte migration.
1 Communities
2 Members
0 Resources
21 MeSH Terms
Altered integrin expression and the malignant phenotype: the contribution of multiple integrated integrin receptors.
Zutter MM, Sun H, Santoro SA
(1998) J Mammary Gland Biol Neoplasia 3: 191-200
MeSH Terms: Breast, Breast Neoplasms, Cell Differentiation, Cell Transformation, Neoplastic, Female, Humans, Integrins, Models, Biological, Receptors, Collagen
Show Abstract · Added February 16, 2014
The integrins are a family of cell surface adhesion receptors that mediate adhesion to either components of the extracellular matrix or to other cells. The beta1 family of integrins represent the major class of cell substrate receptors with specificities primarily for collagens, laminins, and fibronectins. The role of the integrin family of cell surface adhesion receptors in normal mammary gland morphogenesis and the contributions of altered integrin receptor expression to the invasive and metastatic phenotype have been the primary focus of our lab, as well as a number of other laboratories. The alpha2beta1 integrin is expressed at high levels by normal differentiated epithelial cells including those of the normal breast. Using breast cancer as a model, we evaluated changes in integrin expression in malignancy. We and other investigators made the key observation that alpha2beta1 integrin expression is decreased in adenocarcinoma of the breast in a manner that correlates with the stage of differentiation. Studies of other adenocarcinomas have yielded similar results. When the alpha2beta1 integrin was reexpressed in a poorly differentiated mammary carcinoma that expressed no detectable alpha2 integrin subunit, a dramatic reversion of malignant phenotype to a differentiated epithelial phenotype was observed, indicating a critical role for alpha2beta1 expression in mammary gland differentiation. Other laboratories using monoclonal antibodies to competitively inhibit alpha2beta1 integrin adhesion or oncogenic transformation using c-erb2 have confirmed the important role of that alpha2beta1 integrin in mammary gland morphogenesis. Re-expression of the alpha2beta1 integrin also results in upregulation of both the alpha6 and beta4 integrin subunits. To determine the contribution of enhanced alpha6 and beta4 integrin expression to the abrogation of the malignant phenotype by alpha2beta1 integrin expression, we have now separately re-expressed the human alpha6 or beta4 integrin subunit in the breast cancer model.
1 Communities
2 Members
0 Resources
9 MeSH Terms
Role of the alpha1 and alpha2 integrin cytoplasmic domains in cell morphology, motility and responsiveness to stimulation by the protein kinase C pathway.
Wang H, Gai Q, Yang X, Li Z, Linders B, Santoro SA, Zutter MM
(2000) Cell Adhes Commun 7: 281-97
MeSH Terms: Antigens, CD, Cell Adhesion, Cell Movement, Cell Size, Collagen, Cytoplasm, DNA, Complementary, Flow Cytometry, Gene Expression, Hematopoietic Stem Cells, Humans, Integrin alpha1, Integrin alpha2, Integrins, K562 Cells, MAP Kinase Signaling System, Phosphatidylinositol 3-Kinases, Protein Kinase C, Protein Structure, Tertiary, Receptors, Collagen, Recombinant Fusion Proteins
Show Abstract · Added February 16, 2014
The alpha1beta1 and alpha2beta1 integrins, extracellular matrix receptors for collagens and/or laminins, have similarities in structure and ligand binding. Recent studies suggest that the two receptors mediate distinct post-ligand binding events and are not simply redundant receptors. To discern the mechanisms by which the two receptors differ, we focused on the roles of the cytoplasmic domains of the alpha subunits. We expressed either full-length alpha1 integrin subunit cDNA (X1C1), full-length alpha2 integrin subunit cDNA (X2C2), chimeric cDNA composed of the extracellular and transmembrane domains of alpha2 subunit and the cytoplasmic domain of alpha1 (X2C1), chimeric cDNA composed of the extracellular and transmembrane domains of alpha1 subunit and the cytoplasmic domain of alpha2 (X1C2), alpha1 cDNA truncated after the GFFKR sequence (X1C0) or alpha2 cDNA truncated after the GFFKR sequence (X2C0) in K562 cells. Although the cytoplasmic domains of the alpha1 and alpha2 subunits were not required for adhesion, the extent of adhesion at low substrate density was enhanced by the presence of either the alpha1 or alpha2 cytoplasmic tail. Spreading was also influenced by the presence of an alpha subunit cytoplasmic tail. Activation of the protein kinase C pathway with phorbol dibutyrate-stimulated motility that was dependent upon the presence of the alpha2 cytoplasmic tail. Both the phosphatidylinosotide-3-OH kinase and the mitogen-activated protein kinase pathways were required for phorbol-activated, alpha2-cytoplasmic tail-dependent migration.
1 Communities
2 Members
0 Resources
21 MeSH Terms
Determinants of ligand binding specificity of the alpha(1)beta(1) and alpha(2)beta(1) integrins.
Dickeson SK, Mathis NL, Rahman M, Bergelson JM, Santoro SA
(1999) J Biol Chem 274: 32182-91
MeSH Terms: Amino Acid Sequence, Binding Sites, Cloning, Molecular, Collagen, Enzyme-Linked Immunosorbent Assay, Escherichia coli, Humans, Integrin alpha1beta1, Integrin beta1, Integrins, Ligands, Models, Molecular, Molecular Sequence Data, Protein Conformation, Receptors, Collagen, Structure-Activity Relationship
Show Abstract · Added March 5, 2014
The alpha(1)beta(1) and alpha(2)beta(1) integrins are cell surface collagen receptors. Cells expressing the alpha(1)beta(1) integrin preferentially adhere to collagen IV, whereas cells expressing the alpha(2)beta(1) integrin preferentially adhere to collagen I. Recombinant alpha(1) and alpha(2) integrin I domains exhibit the same collagen type preferences as the intact integrins. In addition, the alpha(2) integrin I domain binds echovirus 1; the alpha(1) I domain does not. To identify the structural components of the I domains responsible for the varying ligand specificities, we have engineered several alpha(1)/alpha(2) integrin I domain chimeras and evaluated their virus and collagen binding activities. Initially, large secondary structural components of the alpha(2) I domain were replaced with corresponding regions of the alpha(1) I domain. Following analysis in echovirus 1 and collagen binding assays, chimeras with successively smaller regions of alpha(1) I were constructed and analyzed. The chimeras were analyzed by ELISA with several different alpha(2) integrin monoclonal antibodies to assess their proper folding. Three different regions of the alpha(1) I domain, when present in the alpha(2) I domain, conferred enhanced collagen IV binding activity upon the alpha(2) I domain. These include the alpha3 and alpha5 helices and a portion of the alpha6 helix. Echovirus 1 binding was lost in a chimera containing the alphaC-alpha6 loop; higher resolution mapping identified Asn(289) as playing a critical role in echovirus 1 binding. Asn(289) had not been implicated in previous echovirus 1 binding studies. Taken together, these data reveal the existence of multiple determinants of ligand binding specificities within the alpha(1) and alpha(2) integrin I domains.
1 Communities
1 Members
0 Resources
16 MeSH Terms
Collagen receptor control of epithelial morphogenesis and cell cycle progression.
Zutter MM, Santoro SA, Wu JE, Wakatsuki T, Dickeson SK, Elson EL
(1999) Am J Pathol 155: 927-40
MeSH Terms: Animals, Blotting, Western, Cell Adhesion, Cell Cycle, Cell Differentiation, Cell Division, Cell Line, Clone Cells, Collagen, Epithelial Cells, Female, Fibronectins, Flow Cytometry, Fluorescent Antibody Technique, Humans, Integrins, Mammary Glands, Animal, Mice, Receptors, Collagen
Show Abstract · Added February 16, 2014
To define the unique contributions of the alpha subunit cytoplasmic tails of the alpha(1)beta(1) and alpha(2)beta(1) integrin to epithelial differentiation and branching morphogenesis, a variant NMuMG cell line lacking alpha(1)beta(1) and alpha(2)beta(1) integrin expression was stably transfected with the full-length alpha(2) integrin subunit cDNA (X2C2), chimeric cDNA consisting of the extracellular and transmembrane domains of the alpha(2) subunit and the cytoplasmic domain of the alpha(1) subunit (X2C1), or alpha(2) cDNA truncated after the GFFKR sequence (X2C0). The X2C2 and X2C1 transfectants effectively adhered, spread, and formed focal adhesion complexes on type I collagen matrices. The X2C0 transfectants were less adherent to low concentrations of type I collagen, spread less well, and formed poorly defined focal adhesion complexes in comparison to the X2C2 and X2C1 transfectants. The X2C2 and X2C1 transfectants but not the X2C0 transfectants proliferated on collagen substrates. Only the X2C2 transfectants developed elongate branches and tubules in three-dimensional collagen gels and migrated on type I collagen. These findings suggest a unique role for the alpha(2) integrin cytoplasmic domain in postligand binding events and cooperative interactions with growth factors that mediate epithelial differentiation and branching morphogenesis. Either intact alpha(1) or alpha(2) integrin subunit cytoplasmic domain can promote cell cycle progression.
1 Communities
2 Members
0 Resources
19 MeSH Terms