ABSTRACT
The covalent modification of a protein on a Tyr residue serves several important functions. First, tyrosine phosphorylation of an enzyme may regulate its activity. This is typified by the phosphorylation of the activating loop Tyr residue in a PTK, which leads to activation of the kinase domain, and by the phosphorylation of a C-terminal Tyr residue by Csk, which functions to shut down the kinase (Levinson et al. 2008). Second, phosphorylation may alter the subcellular localization of a protein. For instance, the activation and nuclear retention of the STAT transcription factors are regulated by homodimerization mediated by tyrosine phosphorylation (Wenta et al. 2008). Third, phosphorylation may lead to endocytosis or degradation of a protein. In this regard, the phosphorylation of a C-terminal tyrosine residue on the EGF receptor triggers the binding of the E3 ligase Cbl and subsequent ubiquitination and degradation of the receptor (Sweeney and Carraway 2004). And last, and perhaps most relevant to this chapter, phosphorylation creates docking sites for proteins harboring a phosphotyrosine-recognition domain such that a signal initiated at a PTK may be transduced to downstream molecules efficiently and with high fidelity. A prototypical example is found on insulin receptor substrate 1 (IRS-1), which is phosphorylated on multiple tyrosine residues by the insulin receptor following its activation. This effectively creates multiple docking sites for the recruitment of downstream signaling molecules such as Grb2, SHP2, and PI3K (Ogawa, Matozaki, and Kasuga 1998). Together with other modular domains, pTyr-binding modules provide an effective means by which to form elaborate and highly regulated pathways and networks for signal integration and diversification (Kaneko, Li, and Li 2008; Li 2005; Pawson, Gish, and Nash 2001; Pawson and Scott 2005; Schlessinger and Lemmon 2003; Wiggin, Fawcett, and Pawson 2005).
