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. Historical perspective It has been 20 years since RACK1 was cloned as the first identified binding protein for Protein Kinase C (PKC), and the road the Mochly-Rosen group took toward its discovery was not trivial. The role of scaffolding proteins in the temporal and spatial regulation of signal transduction seems obvious today, however, this was not the case in the late 1980s when Prof. Daria Mochly-Rosen developed the hypothesis that anchoring/scaffolding proteins control the specificity of substrate phosphorylation and function of Protein Kinase C (PKC) isozymes. An alpha phage display library/overlay assay strategy was used to identify binding proteins that interact with active PKC isoforms. To this day Dr. Ron remembers when one gene product was identified and was termed RACK1 for Receptor for Activated C Kinase RACK1 as a scaffolding protein The conserved seven blade propeller structure of RACK1 facilitates the folding order into constituent propeller blades. These propeller blades are intrinsic to RACK1's protein binding capacity and allow RACK1 to function as a signaling hub RACK1: a scaffolding protein with a central role in transcription, epigenetics & translation RACK1 has a strong effect on transcription and translation by acting at critical points; principally the ribosomal small subunit and via nuclear translocation and regulation of chromatin and transcriptional complexes RACK1 and cytoskeletal proteins: a new frontier The cellular cytoskeleton, whose major components comprise of actin, microtubules and intermediate filaments, maintains cellular integrity and regulates multiple cellular functions including migration RACK1 as a potential therapeutic target As the number of binding partners and validated cellular functions for RACK1 has increased, so has its link with an array of disease states [38] are amongst the first describing beta-propeller/small molecule complexes. Interestingly, the report by Senisterra et al. Concluding comments There are, of course, numerous remaining questions that are of great interest. For example, how can one protein play such an important role in many and diverse biological functions? Is it possible that a number of RACK1 binding partners share common binding sites on RACK1? Is RACK1 function and/or expression levels regulated by posttranslational modifications such as phosphorylation, sumoylation and ubiquitination? Does RACK1 contribute to a large number of disease states and can RACK1 be used as a target for drug development? These are exciting times for RACK1 biologists. As more and more research areas converge on RACK1, we can expect answers to these questions to unfold. RACK1 biology would benefit greatly from detailed mechanistic mathematical modelling and quantitative experimentation to help us comprehend how RACK1 functions in systems biology, beyond its role as a scaffolding protein. We look forward to the next RACK1 conference, which we have no doubt will bring more exciting new data on the role of our favorite protein in cellular functions
