Accessory proteins in signal transduction: scaffold proteins and beyond

In these four minireviews, the field of scaffold proteins and proteins of similar molecular ⁄ cellular functions is overviewed. Although these proteins represent a very broad and loosely defined family in both functional and structural terms, the overall aim of the series is to demonstrate certain unifying principles. It is shown that the essence of the function of all proteins in this broad functional class is to bind and bring into proximity two or more signaling proteins, thereby coordinating and regulating signaling events in the cell. The minireviews in this series discuss in detail the four categories, docking, anchoring, scaffold and adaptor proteins, and also other proteins not usually considered to belong to these broad functional categories. The first minireview by Buday and Tompa gives a brief introduction concerning scaffold proteins and related molecules, with the emphasis on adaptor proteins. Central to our concept is that adaptor proteins represent a rather simple solution to this signaling principle. Adaptors, such as Grb2 and Nck1, usually contain two protein–protein interaction domains or regions, connecting two signaling proteins without the formation of a large complex. The second minireview by Brummer, Schmitz-Peiffer and Daly shows that docking proteins were originally classified as signal transducers that exhibit a membrane-targeting region, and multiple Tyr-phosphorylation sites that function as binding sites for SH2 domains of downstream effectors. Because of this layout, these proteins ‘dock’ to the plasma membrane next to an activating Tyr-kinase receptor and initiate a signaling cascade. Classical examples, such as Gab, IRS and FRS, are discussed. It will also be shown that a similar function can be fulfilled by LAT, which has a bona fide transmembrane region. By contrast, p130Cas exhibits an N-terminal SH3 domain rather than a membrane-localization domain. In this sense, this protein is close in function to anchoring proteins, discussed in the third minireview by Logue and Scott. These proteins were originally defined as signaling proteins assembling multiprotein complexes containing protein kinase A, protein phosphatase(s), phosphodiesterase(s) and other molecules in cAMP signaling. Other second-messenger pathways can also be ‘anchored’, thus relevant examples contain not only AKAP150 and mAKAP, but also RACK1 in protein kinase C signaling. The difference between these previous categories and scaffold proteins is mostly semantic, as outlined in the concluding minireview by Alexa, Varga and Reményi. Scaffolds are thought to actively organize signaling complexes with properties different from the simple summation of those of their components. The most notable ones of this category, ste5, KSR, PSD95, DLG1 and caskin1, are discussed in detail. In the introductory minireview we suggest that the actual functional modes these examples represent segregate into three practical categories, simple proteins binding two partners together (adaptors), larger multidomain proteins targeting and regulating more proteins in complex ways (scaffold ⁄ anchoring proteins), and proteins localizing partners at the cell membrane (docking proteins). It is also made clear, however, that the categories cover a continuum, and given the resulting ambiguity in functional definition and elevated pace of discovery, the field is in a state of continuous advance and expansion. As a result, we anticipate that many proteins not usually considered as scaffolds, such as regulatory proteins with catalytic activity, phosphatase targeting subunits, and many more, will soon be included in an extended classification scheme.