Evidence that phosphorylation of the microtubule - associated protein Tau by SAPK 4 / p 38 δ at Thr 50 promotes microtubule assembly

Tau protein belongs to the family of microtubule-associated proteins. It is expressed mainly in neurons, where it is believed to play major regulatory roles in the organization and integrity of the cytoskeletal network. In adult human brain, six Tau isoforms are produced from a single gene by alternative mRNA splicing. They differ by having three or four conserved repeats, located in tandem in the C-terminal region, and no, one or two insertions in the N-terminal portion (Goedert et al., 1989a; Goedert et al., 1989b). The repeats constitute the microtubule-binding domains of Tau (Lee et al., 1989). Tau binds to β-tubulin through these repeats and promotes microtubule assembly (Kar et al., 2003), but may also participate in other cellular processes, such as the linking of signal-transduction pathways to the cytoskeleton (Lee et al., 1998). Tau is functionally modulated by phosphorylation and is highly phosphorylated in several neurodegenerative diseases (Goedert, 2001). It has been demonstrated that the ability of Tau to bind to and stabilise microtubules correlates inversely with its phosphorylation, which may in turn facilitate self-(PHF-Tau) is the major component of the paired helical filaments (PHFs) that make up the neurofibrillary tangles of Alzheimer's disease (Goedert, 2001). Protein chemical and immunochemical studies have identified 25 phosphorylation