Focus Issue: Cellular Regulation Through Protein Interaction Domains

One of the major themes that has emerged in the last 15 years of research into mechanisms of cellular regulation has been the realization of the importance of protein interaction domains as distinct modules that function to determine the interaction partners of various signaling proteins. Understanding the properties of these domains is essential to understanding signaling, and the implications of this basic characteristic of signaling mechanisms are vast. A Review by Pawson and Nash in Science this week provides an overview of signaling domains and their function. They explain how mixing and matching of modules allows formation of versatile molecular machines that mediate regulation of all sorts of biological processes. The elucidation of these structural elements helps explain specificity and dynamic regulation in cell signaling systems, has opened the way for genome-wide analysis of protein interaction networks, provides insight into the evolution of cellular regulatory mechanisms, and may offer new promise for the development of therapeutic agents that target such key regulatory interactions. The Review in Science serves as an introduction and cornerstone for a more comprehensive treatment of protein interaction domains at Science's STKE . This focus issue features the first three in a series of Reviews and Perspectives at STKE that investigate in more detail specific domains or specific sets of domains that share similar functions. We will be adding regularly to this set of updateable Reviews (see [Domains Articles][1]) to provide a centralized resource where STKE users can make sense of the cell's repertoire of signaling modules, which currently number at least 140 on the PROSITE database of protein families and domains. To start off this series, STKE presents two reviews that feature protein-protein interaction motifs and one review that discusses proteins that participate in cellular signaling that also contain or interact with proteins that have RNA binding motifs. The Review by Zarrinpar et al . details the structural basis for the interactions that occur in proteins that recognize proline-rich motifs. The SH3, WW, and EVH1 domains are described in detail. Don't miss the animated figures associated with this Review, which greatly facilitate understanding of the similarities and differences in the mechanisms of proline recognition by these domains. Proline recognition plays crucial roles in cell signaling processes by controlling such processes as protein activation, localization, assembly, and degradation. In Nourry et al ., the spotlight is on the PDZ domain, a protein assembly domain especially important in organizing protein complexes in specialized subcellular compartments of polarized cells, such as the pre- and postsynaptic densities in neurons and the apical and basolateral surfaces of epithelial cells. The authors also discuss the biological and medical relevance of PDZ proteins as determined through genetic models implicating disruption of PDZ proteins in various pathophysiological conditions. Leaving the protein-protein interaction domains and focusing on the protein-RNA interactions, Lasko highlights the proteins that integrate cellular signaling pathways with RNA processing, transport, and metabolism. A look at these proteins shows how the modular nature of protein domains can be used to add another layer to the regulation of gene expression. By combining other motifs common in signaling proteins such as protein phosphorylation motifs and protein-protein interaction motifs, RNA binding domains, and domains unique to these RNA regulatory proteins, cells can regulate gene expression after transcription. RNA binding proteins important in development are described in detail, including the signal transduction and activation of RNA (STAR) proteins, the translational regulator eukaryotic initiation factor 4E-binding protein, and the phosphorylation-dependent endoribonuclease G3BPl. Protein interaction domains, of course, appear often in other published articles at STKE. Interested readers may find useful the Perspectives by Woodside, MacFarlane and Levitan, Sanjay et al ., and Hurley. Woodside discusses research indicating that two classes of signaling receptors--guanine nucleotide-binding protein-coupled receptors (GPCRs) and integrins--contain cytoplasmic domains that can interact specifically with multiple, noncompeting, binding partners. MacFarlane and Levitan discuss the possible roles of leucine zipper motifs, once thought to be present only in transcription factors, in ion channel modulation. The Perspective by Sanjay et al . highlights the Cbl proteins, a family of ubiquitin ligases that down-regulate signaling from receptor and nonreceptor tyrosine kinases, and discusses the structural and biochemical mechanisms underlying Cbl-mediated ubiquitination. Cbl proteins, which contain both phosphotyrosine-binding domains and RING domains, act as adaptor proteins within protein complexes formed after tyrosine kinase activation and mediate the ubiquitination of tyrosine kinases and other proteins in these signaling complexes. The recent Perspective by Hurley concerns GAF domains (cyclic GMP, adenylyl cyclase, FhlA), a large family of domains involved in cyclic nucleotide signaling that recognize and bind both cyclic guanosine 3',5'-monophosphate (cGMP) and cyclic adenosine 3',5'-monophosphate (cAMP). It is instructive to occasionally step back and think in more general terms about how cellular regulatory systems work. These assembled papers document a marvelous diversity of control systems that nature has fashioned largely through the protein modules that determine and modulate a protein's interaction partners. As Pawson and Nash note in their Review in Science , "it is (now) interesting to contemplate the possibility of endowing cells with new properties by using protein interactions to re-specify signaling pathways." Featured in This Focus Issue Related Resources at STKE [1]: http://stke.sciencemag.org/cgi/content/full/sigtrans;2003/179/eg6/DC1