Regulation of α5β1 integrin conformation and function by urokinase receptor binding

Wei, Ying; Czekay, Ralf Peter; Robillard, Liliane; Kugler, Matthias C.; Zhou, Feng; Kim, Kevin K.; Xiong, Jian; Humphries, Martin J.; Chapman, Harold A.

doi:10.1083/jcb.200404112

Cited by 128 publications

(166 citation statements)

References 39 publications

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“…2A). Another possibility is that, analogous to the interaction between uPAR and integrins (34), FcγRIIA may interact with the integrins that exist in the bent conformation, where the α M I-domain would reside very close to the membrane (32). Should this be the case, FcγRIIA, like uPAR, might also be capable of modulating the activity of Mac-1.…”

Section: Discussionmentioning

confidence: 99%

Mac-1 Promotes FcγRIIA-Dependent Cell Spreading and Migration on Immune Complexes

et al. 2006

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The integrin Mac-1 plays a critical role in Fc receptor (FcR)-mediated antibody-dependent cellular cytotoxicity (ADCC). However, the mechanism by which Mac-1 facilitates the functions of FcγRIIA, a major FcR expressed on human leukocytes, is not fully understood. We report here that Mac-1 sustains cell adhesion, enhances cell spreading, and accelerates cell migration on pre-formed immune complexes (ICs) by directly interacting with FcγRIIA but not with the IC substrate. Coupling Mac-1 to FcγRIIA allows FcγRIIA to reside in the leading front of actin polymerization at the filopodial extension, and thus could potentially enhance the FcγRIIA-mediated cell spreading and migration. Direct interaction between Mac-1 and FcγRIIA is demonstrated by co-immunoprecipitation, by cell surface co-localization, and by solid-phase binding assays using recombinant α M I-domain and soluble FcγRIIA. Further mutational analysis identifies the E 253 -R 261 sequence within the α M Idomain as part of the FcγRIIA binding interface within Mac-1. Altogether, these results demonstrate that FcγRIIA recognizes Mac-1 via the α M I-domain but not the lectin domain, a distinct feature from other FcRs, and that Mac-1 binding confers FcγRIIA with the ability to prolong cell adhesion as well as to spread and migrate on the ICs, leading to effective cell killing by ADCC.Receptors recognizing the Fc fragment (FcR) 1 of the immunoglobulin (Ig) molecules are critical to host defense by mediating leukocyte migration toward ICs deposited within the site of infections and by eliciting potent cytolysis of the IC-sensitized targets, such as malignant cells and invading pathogens (1)(2)(3)(4)(5)(6)(7)(8). A number of clinical studies have demonstrated that FcγRIIA (CD32), a major FcR that recognizes the IgG subclass, is essential to the efficacy of several therapeutic antibody-based drugs, including Herceptin for HER-2/neu-positive breast cancer cells, Rituxan for non-hodgkins lymphoma, and the antibodies for melanoma (1,2,9). Yet, inappropriate engagement of FcγRIIA also causes autoimmune diseases in patients undergoing treatment using these therapeutic antibodies (10), and in transgenic mice overexpressing FcγRIIA (11).The FcγRIIA-mediated antibody-dependent cytotoxicity (ADCC) is dependent on both FcγRIIA and the integrin Mac-1 (α M β 2 , CR3, CD11b/CD18) (1,8,12,13). Despite the importance of Mac-1 in the FcγRIIA-mediated leukocyte functions, and the extensive studies conducted on Mac-1 interaction with various FcRs, including FcγRIIIB (CD16), FcαRI (CD89) and FcεRII (CD23), in addition to [14][15][16], the molecular basis underlying Mac-1 recognition of these FcRs is still less understood. Based primarily on inhibition studies using lectin-domain-specific inhibitors such as N-acetyl-D-glucosamine (NADG) (13,15,17), the binding sites within Mac-1 for most of the FcRs are mapped to its lectin-domain in the α subunit. However, as Mac-1's ability to promote FcγRIIA-mediated phagocytosis is insensitive to NADG inhibition (18), the nature of the FcγR...

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Section: Discussionmentioning

confidence: 99%

Mac-1 Promotes FcγRIIA-Dependent Cell Spreading and Migration on Immune Complexes

et al. 2006

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“…68 Binding of a5b1 to urokinase-type plasminogen activator receptors causes a change in the conformation to block the functions of this complex by short b1-chain peptides without affecting a5b1-mediated fibronectin binding. 69 Therefore, the decoy peptide blunted the interaction of renin with (P)RR possibly by changing specific space within the receptor.…”

Section: Interference Of Renin Binding To (P)rr By the Decoymentioning

confidence: 99%

Biochemical properties of renin and prorenin binding to the (pro)renin receptor

Nabi

Suzuki

2009

Hypertens Res

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The discovery of (pro)renin receptor, (P)RR, has made the renin-angiotensin system (RAS) more multifaceted. Interaction of renin and prorenin with this receptor has set a new perspective about the physiological functions, activation mechanism and pathophysiological roles of renin/prorenin. Uses of peptides mimicking the structure of the ligands have been very effective for determining structure-function relationship between the ligands and receptor. The probable pivotal role of decoy peptide region (R 10P IFLKRMPSI 19P ) of prorenin prosegment was suggested for higher binding affinity of prorenin to (P)RR than that of mature renin. Recently, 'hinge' region peptide (S 149 QGVLKEDVF 158 ) in renin/prorenin molecule has been reported. Both renin and prorenin can interact with (P)RR through the 'hinge' region. Furthermore, it has been proposed that prorenin has multiple binding sites whereas renin has a single binding site for (P)RR. To comprehend the activation mechanism of renin and prorenin after receptor binding, it is very important to understand their interaction with the receptor. Several kinds of peptides designed from the regions of the tertiary structure of renin and predicted model of prorenin facilitated the study of the in vitro binding mechanisms for renin and prorenin to (P)RR. Here, a series of recent in vitro studies was reviewed to discuss a possible binding mechanism of renin/prorenin to the (P)RR.

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“…uPA also cleaves its own inhibitor, plasminogen activator inhibitor-1 (PAI-1) (20), and activates hepatocyte growth factor (HGF) (21) and platelet-derived growth factor-D (PDGF-D) (22). Additionally, the uPA/uPAR complex interacts with vitronectin and integrins (18,(23)(24)(25), which modulates the uPAR-mediated interaction between cells and the ECM and/or activates signaling pathways such as PI3K/ AKT (26) and focal adhesion kinase (FAK)/c-Src signaling (27). The level of uPA expression is correlated with the invasive potential and a poor prognosis in various malignant tumors including colon, breast, and stomach (16,28).…”

Section: Mucin 1 (Muc1)mentioning

confidence: 99%

MUC1 Protein Induces Urokinase-type Plasminogen Activator (uPA) by Forming a Complex with NF-κB p65 Transcription Factor and Binding to the uPA Promoter, Leading to Enhanced Invasiveness of Cancer Cells

Mori

Akita

Tanida

et al. 2014

Journal of Biological Chemistry

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Background: Molecular mechanism by which MUC1 promotes cancer cell invasion is unclear. Results: MUC1 forms a complex with NF-B p65 transcription factor and binds to urokinase-type plasminogen activator (uPA) promoter, and thereby induces uPA expression. Conclusion: uPA induced by MUC1 promotes cancer cell invasion. Significance: uPA is a useful target for inhibiting invasion by MUC1-expressing cancer cells.

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Regulation of α5β1 integrin conformation and function by urokinase receptor binding

Cited by 128 publications

References 39 publications

Mac-1 Promotes FcγRIIA-Dependent Cell Spreading and Migration on Immune Complexes

Mac-1 Promotes FcγRIIA-Dependent Cell Spreading and Migration on Immune Complexes

Biochemical properties of renin and prorenin binding to the (pro)renin receptor

MUC1 Protein Induces Urokinase-type Plasminogen Activator (uPA) by Forming a Complex with NF-κB p65 Transcription Factor and Binding to the uPA Promoter, Leading to Enhanced Invasiveness of Cancer Cells

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