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Adaptor Proteins Oncogene (2001) 20, 6270 ± 6272 ã 2001 Nature Publishing Group All rights reserved 0950 ± 9232/01 $15.00 www.nature.com/onc Adaptor proteins Daniel C Flynn*,1,2 1Mary Babb Randolph Cancer Center, West Virginia University, Morgantown, West Virginia, VW 26506-9300, USA; 2Department of Microbiology, Immunology and Cell Biology, West Virginia University, Morgantown, West Virginia, VW 26506-9300, USA Oncogene (2001) 20, 6270 ± 6272. based searching techniques to identify the src-homology 2 (SH2) domain within the amino terminus of the Src Keywords: adaptor; adapter protein and signal trans- nonreceptor tyrosine kinase and veri®ed the presence of duction this domain in other signaling proteins. Biochemical analyses by this group demonstrated the function of the SH2 domain and not long afterward, a number of other protein binding modules were identi®ed, such as the The speci®c and appropriate response of cells to SH3, PH, WW and other domains, as well as the external stimuli requires the integration of multiple conservative structure of the opposing binding motifs. signaling pathways. Stimulation of cell surface recep- Deletional mutagenesis studies by Parsons and collea- tors will initiate cellular signals that are governed by gues as well as others demonstrated that the integrity of post-translational modi®cations (e.g., phosphoryla- these protein-binding modules was functionally re- tions), recruitment of protein binding partners to quired for v-Src or Src527F to transform cells. Here, speci®c subcellular domains, such as the membrane mutations in the SH2 and SH3 domains of v-Src or and through protein ± protein interactions. One of the Src527F were able to block the ability of these major goals of scientists who study signal transduction oncogene products to transform cells while having little is to determine the mechanisms that control cross-talk eect on the high protein tyrosine-speci®c kinase between signaling cascades and to determine how activity of Src that is associated with transformation- speci®city in signaling is achieved. An emerging class competence. Ultimately, the structural analysis of these of proteins that are major contributors to these modular domains using X-ray crystallography or NMR processes are adaptor (or adapter) proteins. Adaptor demonstrated the active centers of these domains and proteins contain a variety of protein-binding modules the mechanisms by which they facilitate protein-protein that link protein-binding partners together and facil- interactions. Collectively, these data demonstrated the itate the creation of larger signaling complexes. By structure and function of protein binding domains and linking speci®c proteins together, cellular signals can be underscored the importance of protein-protein interac- propagated that elicit an appropriate response from the tions in modulating cellular signaling. cell to the environment. Speci®city in signaling would Interestingly, it was the identi®cation of Crk by be achieved by the type of protein binding modules Mayer and colleagues in 1988 that oered an initial encoded by the adaptor protein, the sequence of these example of a signaling protein that encoded little more domains or motifs that would dictate speci®city in than a series of protein binding modules (SH2 and SH3 binding, as well as the subcellular localization and the domains). The ability of Crk to transform cells proximity of binding partners. Thus, adaptor proteins indicated that this protein served to link signaling are positioned to regulate cell signaling in a spatial and proteins together that eected cell growth and cell temporal fashion. shape. Here, we used Crk as a model to de®ne the class An appreciation for the emergence and recognition of of adaptor proteins that are covered in this review. A adaptor proteins can be traced back to earlier studies case could be made for proteins such as Src as having that de®ned functional domains within proteins and the the qualities of an adaptor protein, based on the subsequent identi®cation of their function. Based on observations by Varmus and colleagues of the function studies of glycolytic enzyme pathways, the eminent X- of cSrc in cSrc7/7 cell lines, where the integrity of the ray crystallographer Michael G Rossman proposed that SH2/SH3 domains and not the kinase domain were `domains' within a protein could be de®ned based on important for facilitating cell spreading. However, for (1) homologous sequences in other proteins, (2) our proposes, we limit the de®nition of adaptor structure, (3) spatial separation within a protein, (4) proteins to those proteins that lack an enzymatic function and (5) an active center (Rossman, 1981, Phil. function and contain two or more protein binding Trans. Roy. Soc. Lond., pp. 191 ± 203). Not long modules that serve to link signaling proteins together afterward, Pawsons and colleagues used computer- which eect cell growth and shape. This ability to bind to two or more proteins at once provides the cell with a mechanism to link signaling proteins to each other and *Correspondence: DC Flynn propagate a cellular signal. Adaptor proteins DC Flynn 6271 We begin this special edition of Oncogene with a modulating cell adhesion and cell migration. Following review of adaptor proteins that promote receptor- the theme of transformation, Bustelo outlines the role mediated signaling, as exempli®ed by the T cell of the Vav family in modulating cellular signals that receptor signaling adaptor proteins, LAT, GADS, eect transformation. The Vav proteins amplify and SLP-76. Wonerow and Watson initiate this series receptor signaling and play a key role in modulating with a discussion of the transmembrane adaptor, LAT, GDP/GTP exchange for Rho/Rac proteins. Here, it is which is recognized to play a central role in linking T pointed out that the Vav family may have co-evolved cell receptor mediated activation of Lck, Fyn and Zap with tyrosine kinases as a mechanism to link changes 70 at the cell membrane to stimulate downstream in the cytoskeletal architecture and gene transcription signaling. McGlade follows with a review of the that concomitantly occur in response to extracellular structure and function of GADS, which serve to link signaling. Tsygankov reviews the adaptor protein Cbl, LAT to SLP-76. Subsequently, Judd and Koretzky which not only facilitates protein interactions, but also describe SLP-76 structure and function in T cell has a role as an E3-ubiquitin ligase that can signaling, as well as the role of this protein in functionally inhibit some protein tyrosine kinases. modulating outside-in signaling through integrin The connection between adaptor proteins and aIIbb3 in collagen-induced platelet activation. Two changes in the cytoskeleton is exempli®ed in the review other interesting examples of adaptor proteins that by Li et al. on the function of Nck/Dock adaptor modulate signals emanating from the cell membrane proteins. Here, Ncka and Nckb appear to play an are intersectins and NHERF. O'Bryan describes the important role in linking cell surface receptor signaling intersectins and their role in facilitating endocytosis to the actin-based cytoskeleton as a binding partner for following receptor activation. Lastly, Voltz et al. Pak. Continuing the theme of adaptor proteins and the describe the role of an interesting Na+/H+ ion cytoskeleton, four review articles follow that evolved exchange regulatory factor called NHERF, which from work with the Src oncoprotein by Parsons and contains tandem PDZ domains and can bind to the colleagues. In 1989, Parsons and colleagues proposed ERM family of cytoskeletal adaptor proteins. that one or more of the tyrosine phosphorylated Although NHERF was originally described as a substrates in Src-transformed cells may play a key role regulator of Na+/H+ exchangers, it is now evident in modulating the eects of Src upon changes in cell that this protein plays an important role in cellular shape associated with transformation. To this end, they growth by regulating the localization and turnover of isolated tyrosine phosphorylated substrates from Src G-protein coupled receptors, PDGF receptor and other transformed cells, generated antibodies against these ion transporters. substrates and cloned and identi®ed these tyrosine- The focus of these reviews then shift to downstream phosphorylated substrates. From this line of experi- signaling and ampli®cation of cellular signals. Han et mentation, pp130cas, pp125FAK, AFAP-110, pp85 al. review the Grb7 family of proteins, an emerging cortactin and the cadherin-associated protein pp120ctn family of adaptor proteins, which may play an were identi®ed. Notably, each of these tyrosine- important role in breast cancer and cell migration. phosphorylated substrates are associated with the Ravichandran follows this with a review of Shc, which actin-based cytoskeleton, which was intriguing given plays a key role in modulating signals that direct Map that the disruption of actin ®laments is a hallmark for kinase activation. Tzivion follows with a review of the transformation by Src. This section begins with a 14-3-4 signaling protein, which bind to ser/thr review of the SH3-containing protein, Cortactin, by phosphorylated residues in a speci®c fashion analogous Weed and Parsons. Cortactin appears to play an to SH2 domains and plays a key role in regulating important role in regulating tyrosine phosphorylated proteins involved in intracellular signaling, apoptosis signal transduction and cortical actin ®lament assem- and various transcription factors, by altering the bly. Interestingly, cortactin also appears to work in targeting of these proteins. Schechtman and Mochly- concert with Arp2/3 mediated actin polymerization, Rosen review the family of PKC binding partners indicating a role for cortactin in regulating actin termed `RACKS' and their ability to target the binding ®lament integrity at the cell membrane. This is and localization of speci®c PKC isoforms, as well as followed by a review from Baisden et al. on the actin being able to bind other signaling proteins, and their ®lament associated protein, AFAP-110.
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