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This perspective summarises the first and long overdue RACK1 meeting held at the University of Limerick, Ireland, May 2013, in which RACK1s role in the immune system, the heart and the brain were discussed and its contribution to disease states such as cancer, cardiac hypertrophy and addiction were described. RACK1 is a scaffolding protein and a member of the WD repeat family of proteins. These proteins have a unique architectural assembly that facilitates protein anchoring and the stabilisation of protein activity. A large body of evidence is accumulating which is helping to define the versatile role of RACK1 in assembling and dismantling complex signaling pathways from the cell membrane to the nucleus in health and disease. In this commentary, we first provide a historical perspective on RACK1. We also address many of the pertinent and topical questions about this protein such as its role in transcription, epigenetics and translation, its cytoskeletal contribution and the merits of targeting RACK1 in disease.

Abstract This perspective summarises the first and long overdue RACK1 meeting held at the University of Limerick, Ireland, May 2013, in which RACK1’s role in the immune system, the heart and the brain were discussed and its contribution to disease states such as cancer, cardiac hypertrophy and addiction were described. RACK1 is a scaffolding protein and a member of the WD repeat family of proteins. These proteins have a unique architectural assembly that facilitates protein anchoring and the stabilisation of protein activity. A large body of evidence is accumulating which is helping to define the versatile role of RACK1 in assembling and dismantling complex signaling pathways from the cell membrane to the nucleus in health and disease. In this commentary, we first provide a historical perspective on RACK1. We also address many of the pertinent and topical questions about this protein such as its role in transcription, epigenetics and translation, its cytoskeletal contribution and the merits of targeting RACK1 in disease.

Summary: The recruitment of T cells to tissues and their retention there are essential processes in the pathogenesis of many autoimmune and inflammatory diseases. The mechanisms regulating these processes have become better understood over the past three decades and are now recognized to involve temporally and spatially specific interactions between cell-adhesion molecules. These include integrins, which are heterodimeric molecules that mediate in-to-out and out-to-in signalling in T cells, other leukocytes, and most other cells of the body. Integrin signalling contributes to T-cell circulation through peripheral lymph nodes, immunological synapse stability and function, extravasation at the sites of inflammation, and T-cell retention at these sites. Greater understanding of the contribution of integrin signalling to the role of T cells in autoimmune and inflammatory diseases has focused much attention on the development of therapeutics that target T-cell integrins. This literature review describes the structure, activation, and function of integrins with respect to T cells, then discusses the use of integrin-targeting therapeutics in inflammatory bowel disease, multiple sclerosis, and psoriasis. Efficacy and safety data from clinical trials and post-marketing surveillance are presented for currently approved therapeutics, therapeutics that have been withdrawn from the market, and novel therapeutics currently in clinical trials. This literature review will inform the reader of the current means of targeting T-cell integrins in autoimmune and inflammatory diseases, as well as recent developments in the field. Activated T cells bind to the endothelium using activated integrins as part of the multi-step process of extravasation. The expression of specific repertoires of adhesion molecules on T cells and the endothelium mediates spatial and temporal specificity of extravasation. The role of integrins in the extravasation of activated T cells can be therapeutically inhibited in multiple sclerosis, psoriasis, and inflammatory bowel disease. Graphical Abstract [ABSTRACT FROM AUTHOR]

To metastasize, tumor cells must adopt different morphological responses to resist shear forces encountered in circulating blood and invade through basement membranes. The Rho and Ras GTPases play a critical role in regulating this dynamic behavior. Recently, we demonstrated shear-induced activation of adherent esophageal metastatic cells, characterized by formation of dynamic membrane blebs. Although membrane blebbing has only recently been characterized as a rounded mode of cellular invasion promoted through Rho kinase (ROCK), the role of shear forces in modulating membrane blebbing activity is unknown. To further characterize membrane blebbing in esophageal metastatic cells (OC-1 cell line), we investigated the role of shear in cytoskeletal remodeling and signaling through ROCK and Ras. Our results show that actin and tubulin colocalize to the cortical ring of the OC-1 cell under static conditions. However, under shear, actin acquires a punctuate distribution and tubulin localizes to the leading edge of the OC-1 cell. We show for the first time that dynamic bleb formation is induced by shear alone independent of integrin-mediated adhesion (P < 0.001, compared with OC-1 cells). Y-27632, a specific inhibitor of ROCK, causes a significant reduction in shear-induced bleb formation and inhibits integrin [[alpha].sub.v][[beta].sub.3]-Ras colocalization at the leading edge of the cell. Direct measurement of Ras activation shows that the level of GTP-bound Ras is elevated in sheared OC-1 cells and that the shear-induced increase in Ras activity is inhibited by Y-27632. Finally, we show that shear stress significantly increases OC-1 cell invasion (P < 0.007), an effect negated by the presence of Y-27632. Together our findings suggest a novel physiological role for ROCK and Ras in metastatic cell behavior. cytoskeletal remodeling; dynamic blebs

Ribosomes coordinate spatiotemporal control of gene expression, contributing to the acquisition and maintenance of cancer phenotype. The link between ribosomes and cancer is found in the roles of individual ribosomal proteins in tumorigenesis and cancer progression, including the ribosomal protein, receptor for activated C kinase 1 (RACK1). RACK1 regulates cancer cell invasion and is localized in spreading initiation centres, structural adhesion complexes containing RNA binding proteins and poly‐adenylated mRNAs that suggest a local translation process. As RACK1 is a ribosomal protein directly involved in translation and in breast cancer progression, we propose a new molecular mechanism for breast cancer cell migration and invasion, which considers the molecular differences between epithelial and mesenchymal cell profiles in order to characterize and provide novel targets for therapeutic strategies. Hence, we provide an analysis on how ribosomes translate cancer progression with a final focus on the ribosomal protein RACK1 in breast cancer. LINKED ARTICLES: This article is part of a themed issue on New avenues in cancer prevention and treatment (BJP 75th Anniversary). To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.12/issuetoc [ABSTRACT FROM AUTHOR]

Abstract Background The progression from Barrett's metaplasia to adenocarcinoma is associated with the acquirement of an apoptosis-resistant phenotype. The bile acid deoxycholate (DCA) has been proposed to play an important role in the development of esophageal adenocarcinoma, but the precise molecular mechanisms remain undefined. The aim of this study was to investigate DCA-stimulated COX-2 signaling pathways and their possible contribution to deregulated cell survival and apoptosis in esophageal adenocarcinoma cells. Methods Following exposure of SKGT-4 cells to DCA, protein levels of COX-2, MAPK and PARP were examined by immunoblotting. AP-1 activity was assessed by mobility shift assay. DCA-induced toxicity was assessed by DNA fragmentation and MTT assay. Results DCA induced persistent activation of the AP-1 transcription factor with Fra-1 and JunB identified as the predominant components of the DCA-induced AP-1 complex. DCA activated Fra-1 via the Erk1/2- and p38 MAPK while Erk1/2 is upstream of JunB. Moreover, DCA stimulation mediated inhibition of proliferation with concomitant low levels of caspase-3-dependent PARP cleavage and DNA fragmentation. Induction of the anti-apoptotic protein COX-2 by DCA, via MAPK/AP-1 pathway appeared to balance the DCA mediated activation of pro-apoptotic markers such as PARP cleavage and DNA fragmentation. Both of these markers were increased upon COX-2 suppression by aspirin pretreatment prior to DCA exposure. Conclusion DCA regulates both apoptosis and COX-2-regulated cell survival in esophageal cells suggesting that the balance between these two opposing signals may determine the transformation potential of DCA as a component of the refluxate.