Beta2 integrin/ICAM-1 adhesion molecule interactions in cutaneous inflammation and tumor promotion

Oberyszyn, Tatiana M.; Conti, Claudio J.; Ross, Mary S.; Oberyszyn, Andrew S.; Tober, Kathleen L.; Rackoff, Andrew I.; Robertson, Fredika M.

doi:10.1093/carcin/19.3.445

Cited by 21 publications

(13 citation statements)

References 37 publications

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“…Since the experiments presented here do not directly address conformational alterations in the external domains of integrin α5β1 associated with FN affinity, it is not possible to formally conclude whether GPER-1-enhanced cellular adhesivity occurs via inside-out signaling. However, our findings are consistent with prior observations that have shown that GPCR activation promotes allosteric changes within the ligand-binding domains of β1, β2, and β3 integrins resulting in enhanced adhesive function [63–65]. Our findings suggest that enhanced integrin α5β1 adhesive action of breast cancer cells for FN does not appear to be solely relegated to signaling by GPER-1, as angiotensin II stimulation of breast cancer cells also enhanced fibrillogenesis (Fig.…”

Section: Discussionsupporting

confidence: 92%

“…For example, affinity upregulation of integrin αllbβ 3 for its ligand fibrinogen, a key event in thrombus formation, occurs in response to stimulation of platelets with ADP, epinephrine, or thrombin, whose receptors are GPCRs [62]. Likewise, β1 and β2 integrins on leukocytes exhibit increased affinity for their adhesive proteins in response to a broad array of immunomodulatory substances that act through GPCRs, including, but not limited to, f-Leu-Met-Phe, chemokine, and complement cascade products [63]. Similarly, our findings here indicate that estrogen action via GPER-1 activates integrin α5β1 resulting in its recruitment to focal adhesions (Figs.…”

Section: Discussionmentioning

confidence: 99%

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The G Protein-Coupled Estrogen Receptor-1, GPER-1, Promotes Fibrillogenesis via a Shc-Dependent Pathway Resulting in Anchorage-Independent Growth

et al. 2014

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The G protein-coupled estrogen receptor-1, GPER-1, coordinates fibronectin (FN) matrix assembly and release of heparan-bound epidermal growth factor (HB-EGF). This mechanism of action results in the recruitment of FN-engaged integrin α5β1 to fibrillar adhesions and the formation of integrin α5β1-Shc adaptor protein complexes. Here, we show that GPER-1 stimulation of murine 4 T1 or human SKBR3 breast cancer cells with 17β-estradiol (E2β) promotes the formation of focal adhesions and actin stress fibers and results in increased cellular adhesion and haptotaxis on FN, but not collagen. These actions are also induced by the xenoestrogen, bisphenol A, and the estrogen receptor (ER) antagonist, ICI 182, 780, but not the inactive stereoisomer, 17α-estradiol (E2α). In addition, we show that GPER-1 stimulation of breast cancer cells allows for FN-dependent, anchorage-independent growth and FN fibril formation in “hanging drop” assays, indicating that these GPER-1-mediated actions occur independently of adhesion to solid substrata. Stable expression of Shc mutant Y317F lacking its primary tyrosyl phosphorylation site disrupts E2β-induced focal adhesion and actin stress fiber formation and abolishes E2β-enhanced haptotaxis on FN and anchorage-dependent growth. Collectively, these data demonstrate that E2β action via GPER-1 enhances cellular adhesivity and FN matrix assembly and allows for anchorage-independent growth, cellular events that may allow for cellular survival, and tumor progression.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

The G Protein-Coupled Estrogen Receptor-1, GPER-1, Promotes Fibrillogenesis via a Shc-Dependent Pathway Resulting in Anchorage-Independent Growth

et al. 2014

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“…In addition to its positive feedback, the PECAM-1 homophilic binding intensifies cell junction and gives rise to a tight barrier of endothelium. In the course of diapedesis inclusive of homo- and hetero- interactions of PECAM-1, its crosstalk with integrin α v β 3 establishes adhesion between leukocyte and endothelia cells as well as association between cell adhesion molecules and integrins including VCAM-1/α 4 and ICAM/β 2 181920. Moreover, PECAM-1 could associate with CD38 on lymphocytes and CD177 on neutrophils and may work in the regulation of diapedesis according to previous studies2122.…”

mentioning

confidence: 74%

Structural Basis for Human PECAM-1-Mediated Trans-homophilic Cell Adhesion

Hu¹,

Zhang

et al. 2016

Sci Rep

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Cell adhesion involved in signal transduction, tissue integrity and pathogen infection is mainly mediated by cell adhesion molecules (CAM). One CAM member, platelet–endothelial-cell adhesion molecule-1 (PECAM-1), plays an important role in tight junction among endothelia cells, leukocyte trafficking, and immune response through its homophilic and heterophilic binding patterns. Both kinds of interactions, which lead to endogenous and exogenous signal transmission, are derived from extracellular immunoglobulin-like (IgL) domains and cytoplasmic immunoreceptor tyrosine-based inhibitory motifs (ITIMs) of PECAM-1. To date, the mechanism of trans-homophilic interaction of PECAM-1 remains unclear. Here, we present the crystal structure of PECAM-1 IgL1-2 trans-homo dimer. Both IgL 1 and 2 adopt the classical Ig domain conformation comprised of two layers of β-sheets possessing antiparallel β-strands with each being anchored by a pair of cysteines forming a disulfide bond. The dimer interface includes hydrophobic and hydrophilic interactions. The Small-Angle X-ray Scattering (SAXS) envelope of PECAM-1 IgL1-6 supported such a dimer formation in solution. Cell adhesion assays on wildtype and mutant PECAM-1 further characterized the structural determinants in cell junction and communication.

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“…These genes encode cytokines, chemokines, kinases, and cell-adhesion molecules, including TNF-α (21), IL-8 (22), mitogenactivated protein kinase kinase kinase 8 (MAP3K8) (23), and integrin β2 (ITGB2) (24), whose roles are widely accepted to be essential in inflammation and tumorigenesis. Therefore, p65 is dimethylated on R30 by PRMT5, which profoundly affects its biological activity.…”

Section: Discussionmentioning

confidence: 99%

PRMT5 dimethylates R30 of the p65 subunit to activate NF-κB

Wang

Miyagi

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

210

221

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The ubiquitous inducible transcription factor NF-κB plays central roles in immune and inflammatory responses and in tumorigenesis. Complex posttranslational modifications of the p65 subunit (RelA) are a major aspect of the extremely flexible regulation of NF-κB activity. Although phosphorylation, acetylation, ubiquitination, and lysine methylation of NF-κB have been well described, arginine methylation has not yet been found. We now report that, in response to IL-1β, the p65 subunit of NF-κB is dimethylated on arginine 30 (R30) by protein-arginine methyltransferase 5 (PRMT5). Expression of the R30A and R30K mutants of p65 substantially decreased the ability of NF-κB to bind to κB elements and to drive gene expression. A model in which dimethyl R30 is placed into the crystal structure of p65 predicts new van der Waals contacts that stabilize intraprotein interactions and indirectly increase the affinity of p65 for DNA. PRMT5 was the only arginine methyltransferase that coprecipitated with p65, and its overexpression increased NF-κB activity, whereas PRMT5 knockdown had the opposite effect. Microarray analysis revealed that ∼85% of the NF-κB-inducible genes that are down-regulated by the R30A mutation are similarly down-regulated by knocking PRMT5 down. Many cytokine and chemokine genes are among these, and conditioned media from cells expressing the R30A mutant of p65 had much less NF-κB-inducing activity than media from cells expressing the wild-type protein. PRMT5 is overexpressed in many types of cancer, often to a striking degree, indicating that high levels of this enzyme may promote tumorigenesis, at least in part by facilitating NF-κB-induced gene expression.histone | mass spectrometry T he NF-κB family is comprised of two protein subfamilies: c-Rel, RelB, and RelA (p65), which include transactivation domains in their C termini, and p100 (p52) and p105 (p50), which include a number of ankyrin repeats in their C termini and have transrepressive functions. All family members include an N-terminal DNA-binding region, the Rel homology domain (1). In the absence of an activating stimulus, NF-κB is located in the cytoplasm in a complex with the inhibitory IκB protein. In the classic pathway of NF-κB activation, extracellular signals activate IκB kinase, which phosphorylates IκBα, leading to its ubiquitination and degradation by proteasomes. NF-κB, liberated from IκB, translocates to the nucleus to regulate its target genes (2). The NF-κB pathway is regulated by means of several different posttranslational modifications, including ubiquitination, phosphorylation, acetylation, sumoylation, and nitrosylation (3). The recent work of several laboratories has revealed the reversible methylation of nonhistone proteins by enzymes that were discovered on the basis of their activities toward histones. For NF-κB, we found that in response to an activating signal, such as treatment with IL-1β, the p65 subunit is reversibly methylated on two specific lysine residues by chromatin remodeling enzymes in ways that profoundly aff...

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Beta2 integrin/ICAM-1 adhesion molecule interactions in cutaneous inflammation and tumor promotion

Cited by 21 publications

References 37 publications

The G Protein-Coupled Estrogen Receptor-1, GPER-1, Promotes Fibrillogenesis via a Shc-Dependent Pathway Resulting in Anchorage-Independent Growth

The G Protein-Coupled Estrogen Receptor-1, GPER-1, Promotes Fibrillogenesis via a Shc-Dependent Pathway Resulting in Anchorage-Independent Growth

Structural Basis for Human PECAM-1-Mediated Trans-homophilic Cell Adhesion

PRMT5 dimethylates R30 of the p65 subunit to activate NF-κB

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