One of the neuropathological hallmarks of Alzheimer's disease is the neurofibrillary tangle, which contains paired helical filaments (PHFs) composed of the microtubule-associated protein tau. Tau is hyperphosphorylated in PHFs, and phosphorylation of tau abolishes its ability to bind microtubules and promote microtubule assembly. Restoring the function of phosphorylated tau might prevent or reverse PHF formation in Alzheimer's disease. Phosphorylation on a serine or threonine that precedes proline (pS/T-P) alters the rate of prolyl isomerization and creates a binding site for the WW domain of the prolyl isomerase Pin1. Pin1 specifically isomerizes pS/T-P bonds and regulates the function of mitotic phosphoproteins. Here we show that Pin1 binds to only one pT-P motif in tau and copurifies with PHFs, resulting in depletion of soluble Pin1 in the brains of Alzheimer's disease patients. Pin1 can restore the ability of phosphorylated tau to bind microtubules and promote microtubule assembly in vitro. As depletion of Pin1 induces mitotic arrest and apoptotic cell death, sequestration of Pin1 into PHFs may contribute to neuronal death. These findings provide a new insight into the pathogenesis of Alzheimer's disease.
Protein-interacting modules help determine the specificity of signal transduction events, and protein phosphorylation can modulate the assembly of such modules into specific signaling complexes. Although phosphotyrosine-binding modules have been well-characterized, phosphoserine- or phosphothreonine-binding modules have not been described. WW domains are small protein modules found in various proteins that participate in cell signaling or regulation. WW domains of the essential mitotic prolyl isomerase Pin1 and the ubiquitin ligase Nedd4 bound to phosphoproteins, including physiological substrates of enzymes, in a phosphorylation-dependent manner. The Pin1 WW domain functioned as a phosphoserine- or phosphothreonine-binding module, with properties similar to those of SRC homology 2 domains. Phosphoserine- or phosphothreonine-binding activity was required for Pin1 to interact with its substrates in vitro and to perform its essential function in vivo.
Phosphorylation of proteins on serine͞threonine residues preceding proline is a key signaling mechanism. The conformation and function of a subset of these phosphorylated proteins is regulated by the prolyl isomerase Pin1 through isomerization of phosphorylated Ser͞Thr-Pro bonds. Although young Pin1 ؊/؊ mice have been previously shown to develop normally, we show here that they displayed a range of cell-proliferative abnormalities, including decreased body weight and testicular and retinal atrophies. Furthermore, in Pin1 ؊/؊ adult females, the breast epithelial compartment failed to undergo the massive proliferative changes associated with pregnancy. Interestingly, many of these Pin1-deficient phenotypes such as retinal hypoplasia and mammary gland impairment are also the characteristic of cyclin D1-deficient mice. Cyclin D1 levels were significantly reduced in many tissues in Pin1-deficient mice, including retina and breast epithelial cells from pregnant mice. Moreover, Pin1 directly bound to cyclin D1 phosphorylated on Thr-286 -Pro increased cyclin D1 in the nucleus and stabilized cyclin D1. These results indicate that Pin1 positively regulates cyclin D1 function at the transcriptional level, as demonstrated previously, and also through posttranslational stabilization, which together explain why Pin1 loss-of-function phenotypes in the mouse resemble cyclin D1-null phenotypes. Our results provide genetic evidence for an essential role of Pin1 in maintaining cell proliferation and regulating cyclin D1 function. P hosphorylation of proteins on serine͞threonine residues preceding proline (pSer͞Thr-Pro) is a key regulatory mechanism for the control of various cellular processes, including cell division and transcription (for reviews see refs. 1-3). The pSer͞Thr-Pro moiety in peptides and proteins exists in two distinct cis and trans conformations, whose conversion is catalyzed specifically by Pin1 (4, 5). Pin1 is a cis͞trans peptidyl-prolyl isomerase that acts only on phosphorylated Ser͞Thr-Pro bonds (6-8). In addition, Pin1 contains an N-terminal WW domain, which functions as a phosphorylated Ser͞Thr-Pro binding module (9, 10). This phosphorylationdependent interaction targets Pin1 to a defined subset of phosphorylated substrates facilitating conformational changes in phosphorylated proteins, thereby regulating their biological function (7,(11)(12)(13)(14)(15)(16)(17)(18)(19)(20). Thus, Pin1-dependent prolyl isomerization is an essential and novel postphosphorylation regulatory mechanism.Given its phosphorylated Ser͞Thr-Pro substrate specificity, Pin1 has also been shown to be essential for maximal cell growth in different systems (4, 5). Interestingly, we have recently found that Pin1 is strikingly overexpressed in most human breast cancer tissues (21,22). Pin1 levels are correlated with cyclin D1 mRNA and protein levels in human cancer tissues. Moreover, Pin1 can activate the cyclin D1 promoter in cell lines via binding phosphorylated c-Jun and -catenin and increasing their transcriptional activity (21,22). The...
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