Biomedical subjects

Greg Finn

Publications and source records attributed to Greg Finn.

6 recordsLinked to original sources

PubMed2006

Negative regulation of interferon-regulatory factor 3-dependent innate antiviral response by the prolyl isomerase Pin1.

Recognition of double-stranded RNA activates interferon-regulatory factor 3 (IRF3)-dependent expression of antiviral factors. Although the molecular mechanisms underlying the activation of IRF3 have been studied, the mechanisms by which IRF3 activity is reduced have not. Here we report that activation of IRF3 is negatively regulated by the peptidyl-prolyl isomerase Pin1. After stimulation by double-stranded RNA, induced phosphorylation of the Ser339-Pro340 motif of IRF3 led to its interaction with Pin1 and finally polyubiquitination and then proteasome-dependent degradation of IRF3. Suppression of Pin1 by RNA interference or genetic deletion resulted in enhanced IRF-3-dependent production of interferon-beta, with consequent reduction of virus replication. These results elucidate a previously unknown mechanism for controlling innate antiviral responses by negatively regulating IRF3 activity via Pin1.

Animals↗

PubMed2006

Regulation of Bruton tyrosine kinase by the peptidylprolyl isomerase Pin1.

Bruton tyrosine kinase (Btk) is expressed in B-lymphocytes. Mutations in Btk cause X-linked agammaglobulinemia in humans. However, the mechanism of activation and signaling of this enzyme has not been fully investigated. We have here shown that the peptidylprolyl cis/trans isomerase (PPIase) Pin1 is a negative regulator of Btk, controlling its expression level by reducing its half-life, whereas the catalytic activity of Btk was unaffected. The negative regulatory effect of Pin1 was observed both in cell lines and in Pin(-/-) mice and was found to be dependent on a functionally intact Btk. This may constitute a feedback loop for the regulation of Btk. The target region in Btk was localized to the pleckstrin homology domain suggesting that interphase phosphorylation of serine 115 (Ser-115) in Btk is required, whereas mitosis phosphorylation of serine 21 (Ser-21) is critical. Accordingly, Pin 1 was shown to associate with Btk through binding to Ser-21 and -115, respectively, both of which lie in a classical Pin1-binding pocket. Using a phosphomitotic antibody, it was found that Btk harbors a bona fide MPM2 epitope corresponding to a phosphorylated serine or threonine residue followed by a proline. Our results indicate that the peptidylprolyl isomerase Pin1 interacts with Btk in a cell cycle-dependent manner, regulating the Btk expression level.

Agammaglobulinaemia Tyrosine Kinase↗

PubMed2006

The prolyl isomerase Pin1 regulates amyloid precursor protein processing and amyloid-beta production.

Neuropathological hallmarks of Alzheimer's disease are neurofibrillary tangles composed of tau and neuritic plaques comprising amyloid-beta peptides (Abeta) derived from amyloid precursor protein (APP), but their exact relationship remains elusive. Phosphorylation of tau and APP on certain serine or threonine residues preceding proline affects tangle formation and Abeta production in vitro. Phosphorylated Ser/Thr-Pro motifs in peptides can exist in cis or trans conformations, the conversion of which is catalysed by the Pin1 prolyl isomerase. Pin1 has been proposed to regulate protein function by accelerating conformational changes, but such activity has never been visualized and the biological and pathological significance of Pin1 substrate conformations is unknown. Notably, Pin1 is downregulated and/or inhibited by oxidation in Alzheimer's disease neurons, Pin1 knockout causes tauopathy and neurodegeneration, and Pin1 promoter polymorphisms appear to associate with reduced Pin1 levels and increased risk for late-onset Alzheimer's disease. However, the role of Pin1 in APP processing and Abeta production is unknown. Here we show that Pin1 has profound effects on APP processing and Abeta production. We find that Pin1 binds to the phosphorylated Thr 668-Pro motif in APP and accelerates its isomerization by over 1,000-fold, regulating the APP intracellular domain between two conformations, as visualized by NMR. Whereas Pin1 overexpression reduces Abeta secretion from cell cultures, knockout of Pin1 increases its secretion. Pin1 knockout alone or in combination with overexpression of mutant APP in mice increases amyloidogenic APP processing and selectively elevates insoluble Abeta42 (a major toxic species) in brains in an age-dependent manner, with Abeta42 being prominently localized to multivesicular bodies of neurons, as shown in Alzheimer's disease before plaque pathology. Thus, Pin1-catalysed prolyl isomerization is a novel mechanism to regulate APP processing and Abeta production, and its deregulation may link both tangle and plaque pathologies. These findings provide new insight into the pathogenesis and treatment of Alzheimer's disease.

Alzheimer Disease↗

PubMed2006

Targeting carcinogenesis: a role for the prolyl isomerase Pin1?

Phosphorylation of proteins on serine or threonine residues that immediately precede proline (pSer/Thr-Pro) is a central signaling mechanism in cell proliferation and transformation. Recent studies indicate that certain pSer/Thr-Pro motifs in native proteins exist in two completely distinct conformations, cis and trans, whose conversion is markedly slowed down upon phosphorylation, but specifically catalyzed by the peptidyl-prolyl cis/trans isomerase Pin1. Importantly, such Pin1-catalyzed conformational changes can have profound effects on the function of many phosphorylation signaling pathways, thereby playing an important role in various cellular processes. Moreover, increasing evidence indicates that aberrant Pin1 function plays an important role in the pathogenesis of some human diseases. Notably, Pin1 is not only overexpressed in a large number of human cancers, but also is an excellent prognostic marker in some cancers. Furthermore, Pin1 overexpression can function as a critical catalyst that amplifies multiple oncogenic signaling pathways during oncogenesis. Moreover, Pin1 overexpression causes cell transformation, centrosome amplification, genomic instability, and tumor development. In contrast, Pin1 knockout in mice prevents certain oncogenes from inducing tumors and Pin1 inhibition in cancer cells suppresses their cell proliferation, transformed phenotype and tumorigenicity in nude mice as well as increases the response to other anticancer agents. These results suggest that Pin1-mediated postphosphorylation regulation may provide a unique opportunity for disrupting oncogenic pathways, and thereby represent an appealing target for novel anticancer therapies.

Catalysis↗

PubMed2005

The Cdk1 complex plays a prime role in regulating N-myc phosphorylation and turnover in neural precursors.

Myc family transcription factors are destabilized by phosphorylation of a conserved amino-terminal GSK-3beta motif. In proliferating cerebellar granule neuron precursors (CGNPs), Sonic hedgehog signaling induces N-myc expression, and N-myc protein is stabilized by insulin-like growth factor-mediated suppression of GSK-3beta. N-myc phosphorylation-mediated degradation is a prerequisite for CGNP growth arrest and differentiation. We investigated whether N-myc phosphorylation and turnover are thus linked to cell cycle exit in primary mouse CGNP cultures and the developing cerebellum. We report that phosphorylation-induced turnover of endogenous N-myc protein in CGNPs increases during mitosis, due to increased priming phosphorylation of N-myc for GSK-3beta. The priming phosphorylation requires the Cdk1 complex, whose cyclin subunits are indirect Sonic hedgehog targets. These findings provide a mechanism for promoting growth arrest in the final cycle of neural precursor proliferation competency, or for resetting the cell cycle in the G1 phase, by destabilizing N-myc in mitosis.

Animals↗

PubMed2005

Phosphorylation-specific prolyl isomerization: is there an underlying theme?

The prolyl isomerase Pin1 is a conserved enzyme that is intimately involved in diverse biological processes and pathological conditions such as cancer and Alzheimer's disease. By catalysing cis-trans interconversion of certain motifs containing phosphorylated serine or threonine residues followed by a proline residue (pSer/Thr-Pro), Pin1 can have profound effects on phosphorylation signalling. The structural and functional differences that result from cis-trans isomerization of specific pSer/Thr-Pro motifs probably underlie most, if not all, Pin1-dependent actions. Phosphorylation-dependent prolyl isomerization by Pin1 remains a unique mode for the modulation of signal transduction. Here, we provide an overview of the plethora of regulatory events that involve this unique enzyme, with a particular focus on oncogenic signalling and neurodegeneration.

Alzheimer Disease↗