A new kinase joins the ranks of those linking a miscreant cell cycle to Alzheimer disease (AD). A June 12 article in press in Neurobiology of Disease shows that PCTAIRE 3, a homolog of Cdc2 kinases, stimulates phosphorylation of the microtubule binding protein tau. The finding suggests that the poorly characterized kinase might play a role in AD and other neurodegenerative diseases.
A. Zara Herskovits and Peter Davies, at the Albert Einstein College of Medicine, Bronx, New York, became interested in PCTAIRE 3 because previous microarray analysis carried out in their lab revealed that the kinase mRNA is elevated in AD brain tissue. Now, using PCTAIRE 3 antibodies, they show that protein levels are also elevated in postmortem temporal cortex from AD brain. More specifically, the authors found that PCTAIRE 3 binds to paired helical fragments (PHFs), the filamentous structures of tau that can go on to form the neurofibrillary tangles that characterize AD and other neurodegenerative diseases such as frontotemporal dementia. Herskovits and Davies isolated PHFs from postmortem tissue by affinity chromatography, and then probed the structures to find PCTAIRE 3. In contrast, they did not detect GSK3β and protein kinase A, two long-studied tau kinases, in the PHFs.
Though a few kinases that bind to PHFs have previously been described, “the definitive identity of each protein has not been established,” write the authors. This makes the identification of PCTAIRE 3 particularly interesting, and yet the kinase does not seem to phosphorylate tau directly. Though the authors found that expressing PCTAIRE 3 in tau-producing Chinese hamster ovary (CHO) cells led to a dramatic increase in tau phosphorylation at tyrosine 231 and serine 235—amino acids that are phosphorylated early during disease pathogenesis in vitro—PCTAIRE 3 had no effect on tau phosphorylation. The results seem to indicate that PCTAIRE 3 stimulates tau phosphorylation indirectly. However, it is worth noting that this kinase has not yet been well characterized, and while the authors used reaction conditions suited to the homologous kinase Cdc2, there is a chance that the immunoprecipitated PCTAIRE 3 used in the in vitro assays was not active under the conditions used. But one thing does seem clear: the kinase domain is essential for the effect on tau, because constructs missing this domain failed to induce tau phosphorylation.
If PCTAIRE 3 does act indirectly on tau, it could do so by stimulating other kinase activity or suppressing phosphatases. If the former, then there may be a new tau kinase lurking out there, because as the authors note, the PCTAIRE 3-stimulated phosphorylation pattern (at T231 and S202 but not S202 or S396) does not match that of any known tau kinase. But a likely binding candidate is already in the wings. Proteomic analysis identified PCTAIRE 3 as a 14-3-3 binding partner (see Meek et al., 2004). The protein 14-3-3 has been implicated in prion- (see ARF related news story) and polyglutamine-linked neurodegenerative diseases (see ARF related news story) and is also found in NFTs and stimulates tau phosphorylation via GSK3β (see Agarwal-Mawal et al., 2003) and cAMP-dependent protein kinase (see Hashiguchi et al., 2000). Whatever the mechanism of action, because it stimulates those early tau phosphorylations, PCTAIRE 3 may become an attractive target for therapeutics that prevent tau pathology.—Tom Fagan
- Meek SE, Lane WS, Piwnica-Worms H. Comprehensive proteomic analysis of interphase and mitotic 14-3-3-binding proteins. J Biol Chem. 2004 Jul 30;279(31):32046-54. PubMed.
- Agarwal-Mawal A, Qureshi HY, Cafferty PW, Yuan Z, Han D, Lin R, Paudel HK. 14-3-3 connects glycogen synthase kinase-3 beta to tau within a brain microtubule-associated tau phosphorylation complex. J Biol Chem. 2003 Apr 11;278(15):12722-8. Epub 2003 Jan 27 PubMed.
- Hashiguchi M, Sobue K, Paudel HK. 14-3-3zeta is an effector of tau protein phosphorylation. J Biol Chem. 2000 Aug 18;275(33):25247-54. PubMed.
No Available Further Reading
- Herskovits AZ, Davies P. The regulation of tau phosphorylation by PCTAIRE 3: implications for the pathogenesis of Alzheimer's disease. Neurobiol Dis. 2006 Aug;23(2):398-408. PubMed.