Integrins are important mammalian receptors involved in normal cellular functions as well as pathogenesis of chronic inflammation and cancer. We propose that integrins are exploited by the gastric pathogen and type-1 carcinogen Helicobacter pylori for injection of the bacterial oncoprotein cytotoxin-associated gene A (CagA) into gastric epithelial cells. Virulent H. pylori express a type-IV secretion pilus that injects CagA into the host cell; CagA then becomes tyrosine-phosphorylated by Src family kinases. However, the identity of the host cell receptor involved in this process has remained unknown. Here we show that the H. pylori CagL protein is a specialized adhesin that is targeted to the pilus surface, where it binds to and activates integrin alpha5beta1 receptor on gastric epithelial cells through an arginine-glycine-aspartate motif. This interaction triggers CagA delivery into target cells as well as activation of focal adhesion kinase and Src. Our findings provide insights into the role of integrins in H.-pylori-induced pathogenesis. CagL may be exploited as a new molecular tool for our further understanding of integrin signalling.

The Helicobacter pylori immunodominant protein, CagA, is associated with severe gastritis and carcinoma. Injection of CagA into gastric epithelial cells by type IV secretion leads to actin-cytoskeletal rearrangements and cell scattering. CagA has been reported to have no role in the induction of transcription factor NF-B and IL-8, which are crucial determinants for chronic inflammation. Here, we provide several lines of evidence showing that CagA is able to induce IL-8 in a time-and strain-dependent manner. We also show that by exchanging specific cagA genes, high IL-8-inducing H. pylori strains could be converted into low inducing strains and vice versa. Our results suggest that IL-8 release induced by CagA occurs via a Ras3 Raf3 Mek3 Erk3 NF-B signaling pathway in a Shp-2-and c-Met-independent manner. Thus, CagA is a multifunctional protein capable of effecting both actin remodeling and potentiation of chemokine release. molecular pathogenesis ͉ pathogenicity island ͉ type IV secretion ͉ virulence

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The paramount importance of the homeostasis of the extracellular matrix for pulmonary function is exemplified by two opposing extremes: emphysema and pulmonary fibrosis. This study examined the putative role of cathepsin K (catK) in the pathology of lung fibrosis in mice and its relevance to the human disease activity. We compared the induction of lung fibrosis by administration of bleomycin. CTSK(-/-) mice deposited significantly more extracellular matrix than control mice. Primary lung fibroblasts derived from CTSK(-/-) mice showed a decreased collagenolytic activity indicating the role of catK in collagen degradation. Interestingly, CTSK(+/+) control mice revealed an increased expression of catK in fibrotic lung regions suggesting a protective role of catK to counter the excessive deposition of collagen matrix in the diseased lung. Similarly, in lung specimens obtained from patients with lung fibrosis fibroblasts expressed larger amounts of catK than those obtained from normal lungs. Activation of human pulmonary fibroblasts in primary cell cultures led to an increased activity of catK through enhanced gene transcription and protein expression and to increased intracellular collagenolytic activity. We believe that this is the first study to show that catK plays a pivotal role in lung matrix homeostasis under physiological and pathological conditions.

Cell migration and invasion require the coordinated regulation of cytoskeletal architectural changes by signaling factors, including the actin-binding protein cortactin. Bacterial and viral pathogens subvert these signaling factors to promote their uptake, spread and dissemination. We show that the gastric pathogen Helicobacter pylori (Hp) targets cortactin by two independent processes leading to its tyrosine dephosphorylation and serine phosphorylation to regulate cell scattering and elongation. The phosphorylation status of cortactin dictates its subcellular localization and signaling partners. Upon infection, cortactin was found to interact with and stimulate the kinase activity of focal adhesion kinase (FAK). This interaction required the SH3 domain and phosphorylation of cortactin at serine 405 and a proline-rich sequence in FAK. Using Hp as a model, this study unravels a previously unrecognized FAK activation pathway. We propose that Hp targets cortactin to protect the gastric epithelium from excessive cell lifting and ensure sustained infection in the stomach.

Summary Host cell invasion of the food-borne pathogenCampylobacter jejuni is one of the primary reasons of tissue damage in humans but molecular mechanisms are widely unclear. Here, we show that C. jejuni triggers membrane ruffling in the eukaryotic cell followed by invasion in a very specific manner first with its tip followed by the flagellar end. To pinpoint important signalling events involved in the C. jejuni invasion process, we examined the role of small Rho family GTPases. Using specific GTPase-modifying toxins, inhibitors and GTPase expression constructs we show that Rac1 and Cdc42, but not RhoA, are involved in C. jejuni invasion. In agreement with these observations, we found that internalization of C. jejuni is accompanied by a time-dependent activation of both Rac1 and Cdc42. Finally, we show that the activation of these GTPases involves different host cell kinases and the bacterial fibronectin-binding protein CadF. Thus, CadF is a bifunctional protein which triggers bacterial binding to host cells as well as signalling leading to GTPase activation. Collectively, our results suggest that C. jejuni invade host target cells by a unique mechanism and the activation of the Rho GTPase members Rac1 and Cdc42 plays a crucial role in this entry process.

Breg emerge as important players in pregnancy; they suppress undesired immune responses from maternal T cells and are therefore important for tolerance acquisition.

Eukaryotic cell adhesion is a fundamental process in tissue development, homeostasis, and disease and is mediated by specific interactions of cell surface receptors with extracellular matrix (ECM) 2 proteins (1-5). The ECM is a meshwork of fibrillar and nonfibrillar components assembled into complex structures such as basement membranes. The latter provide a scaffold for cell adhesion, spreading, and migration. ECM regulates numerous cell functions by activating multiple signaling pathways at the adhesion sites. ECMs, composed of collagens, laminins, and other glycoproteins such as fibronectin (FN), serve as substrates for different adhesion molecules including the integrin family of transmembrane receptors. The assembly of ECM components into functional supramolecular modules is highly regulated (3-7). FN matrix assembly alone is a dynamic cell-driven process in which the soluble FN molecules assemble into insoluble fibrillar polymeric ECM structures (8).FN and integrin receptors play crucial roles in a variety of morphogenetic processes, which are regulated by processes termed outside-in and inside-out signaling cascades (3-5). Deregulation of integrin and FN functions associates with disease development including chronic inflammation, heart failure, cancer, and metastasis (7, 9 -11). The outside-in signaling triggered by ligation of integrin receptors with FN and other ECM components results in the reorganization of cytoskeletal and signaling molecules into complexes of more than 90 proteins (9 -13). This occurs by synergistic processes dependent on integrin aggregation and occupancy, as well as tyrosine phosphorylation. Integrins also cooperate with growth factor receptors such as epidermal growth factor receptor (EGFR) to enhance signaling (14).FN consists of multiple domains (classified types I-III) that show binding specificities for specific cell membrane receptors, collagen, fibrin, and heparin. FN alone is sufficient to induce highly efficient spreading of many mammalian cell types including fibroblast and epithelial cells in vitro. An important functional unit of FN is its RGD tripeptide motif, which acts in