Interaction Domains A Common Theme in Signaling

Interaction domains are essential in signaling from many different types of cell-surface receptors, as well as in cellular events such as the cell cycle, protein and vesicle trafficking, targeted protein degradation, DNA repair, and control of the cytoskeleton. Thus, the SH2 domain serves as a prototype for a growing family of protein-interaction modules (Table 1), some of which specifically recognize posttranslationally modified motifs, in a fashion akin to the selective binding of SH2 and PTB domains to phosphotyrosine-containing sequences [1,31]. A number of domains can bind phosphothreonine/ phosphoserine-containing motifs (i.e., 14-3-3, FHA, MH2, WD40, WW) and thereby mediate the effects of protein-serine/threonine kinases [32]. For example, in a series of interactions analogous to receptor tyrosine kinase signaling, the activated type I TGF0 receptor serine/threonine kinase becomes autophosphorylated within its juxtamembrane region, thereby creating binding sites for the MH2 domain of a regulatory (R-) SMAD protein, which recognizes pSer-X-pSer motifs [33,34]. Subsequent phosphorylation of the R-SMAD itself leads to binding to the MH2 domain of SMAD4 and translocation of the R-SMAD/SMAD-4 complex

Figure 1 The modular nature of proteins containing SH2 or PTB/PID domains; a comparison of the modular protein domains and positional organization of a representative sample of the approximately 162 proteins that contain phosphotyrosine interaction modules and thus represent the key link between activated tyrosine kinases and cellular signaling cascades. The selected proteins demonstrate the variety of cellular functions and pathways in which the proteins containing these interaction modules are implicated. (Additional information on individual domains can be found at http://www.mshri.on.ca/ pawson/researchl.html and http://smart.embl-heidelberg.de/.) Ribbon diagrams show the SH2-C domain of phospholipase-Cy bound to a specific phosphotyrosine-containing peptide (DNDpYPLPDPK) and the PTB domain of Shc bound to an HIIENPQpYFS peptide.

Figure 1 The modular nature of proteins containing SH2 or PTB/PID domains; a comparison of the modular protein domains and positional organization of a representative sample of the approximately 162 proteins that contain phosphotyrosine interaction modules and thus represent the key link between activated tyrosine kinases and cellular signaling cascades. The selected proteins demonstrate the variety of cellular functions and pathways in which the proteins containing these interaction modules are implicated. (Additional information on individual domains can be found at http://www.mshri.on.ca/ pawson/researchl.html and http://smart.embl-heidelberg.de/.) Ribbon diagrams show the SH2-C domain of phospholipase-Cy bound to a specific phosphotyrosine-containing peptide (DNDpYPLPDPK) and the PTB domain of Shc bound to an HIIENPQpYFS peptide.

to the nucleus, where it acts to regulate gene expression (see Chapter 81) [35]. In contrast, bromo- and chromo-domains bind lysine-based motifs (notably in histones) in a fashion dependent on acetylation or methylation, respectively, of the lysine residue and thereby play an important role in chro-matin organization and transcriptional control. Ubiquitin interaction motifs (UIM), a common feature of endocytic proteins, bind mono- or polyubiquitinated sites and appear to regulate protein trafficking to endosomes [36]. Other protein-interaction domains recognize unmodified peptide motifs, such as proline-rich sequences (SH3, WW, and EVH1 domains) [37] or the extreme C-terminal residues of target proteins (PDZ domains) [38].

A separate class of interaction domains (i.e., PH, FYVE, PX, ENTH, FERM, Tubby) recognizes specific phospho-lipids, particularly phosphoinositides, and therefore directs proteins to regions in the plasma membrane enriched for the appropriate phospholipid [39,40]. These phospholipid-binding domains mediate the effects of lipid kinases and phosphatases and function in synchrony with protein-interaction domains. For example, autophosphorylated receptor tyrosine kinases bind the p85 SH2-containing subunit of PI3K, thereby stimulating PI3K to produce PI-3,4,5-P3.

This phospholipid engages the PH domains of intracellular targets such as the serine/threonine protein kinases PKB/Akt and phosphoinositide-dependent protein kinase (PDK1), which consequently are recruited to the membrane, resulting in PKB activation. PKB, in turn, phosphorylates targets that include the pro-apoptotic protein BAD and the transcription factor FKHRL at Ser residues, which subsequently bind 14-3-3 proteins [32]. 14-3-3 binding represses the ability of the phosphorylated proteins to induce apoptosis by sequestering them in the cytoplasm away from their sites of action. Thus, a signaling pathway can be constructed from a series of protein and lipid kinases and a succession of phospho-dependent protein-protein and protein-phospholipid interactions.

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