PIN1

Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 is an is_associated_with::enzyme that in humans is encoded by the PIN1 is_associated_with::gene. (Not to be confused with PIN1 (Pin-formed 1), an is_associated_with::auxin transporter in is_associated_with::Arabidopsis thaliana.)

Pin 1, or peptidyl-prolyl cis/trans is_associated_with::isomerase (PPIase), isomerizes only phospho-Serine/Threonine-Proline motifs. The enzyme binds to a subset of proteins and thus plays a role as a post phosphorylation control in regulating protein function. Studies have shown that the is_associated_with::deregulation of Pin1 may play a pivotal role in various diseases. Notably, the is_associated_with::up-regulation of Pin1 may be implicated in certain is_associated_with::cancers, and the down-regulation of Pin1 may be implicated in is_associated_with::Alzheimer's disease. Inhibitors of Pin1 may have therapeutic implications for cancer and is_associated_with::immune disorders.

Discovery and characterization
The gene encoding Pin1 was identified in 1996 as a result of a genetic/biochemical screen for proteins involved in mitotic is_associated_with::regulation. It was found to be essential for is_associated_with::cell division in some organisms. By 1999, however, it was apparent that Pin1 is_associated_with::knockout mice had a surprisingly mild is_associated_with::phenotype, indicating that the enzyme was not required for cell division per se. Further studies later found that loss of Pin1 in mice displays are not only neuronal degenerative phenotypes but also several abnormalities, similar to those of is_associated_with::cyclin D1-null mice, suggesting the conformation changes mediated by Pin1 may be crucial for cell normal function.

Activation of Pin1
is_associated_with::Phosphorylation of Ser/Thr-Pro motifs in substrates is required for recognition by Pin1. Pin is a small protein at 18 kDa and does not have a nuclear localization or export signal. Substrate interactions and a is_associated_with::WW domain determine subcellular distribution. Expression is induced by growth signals from is_associated_with::E2F transcription factors. Expression levels fluctuate in normal, but not in cancerous cells. Expression is often associated with is_associated_with::cell proliferation. Postranslational modifications such as phosphorylation on Ser16 inhibit the ability of Pin1 to bind substrate, and this inhibitory process may be altered during is_associated_with::oncogenesis. It is hypothesized, but not proven, that Pin1 might also be regulated by proteolytic pathways.

Biological function
Pin1 activity regulates the outcome of proline-directed kinase (e.g. is_associated_with::MAPK, CDK or is_associated_with::GSK3) signalling and consequently regulates cell proliferation (in part through control of cyclin D1 levels and stability) and cell survival. The precise effects of Pin1 depend upon the system: Pin1 accelerates is_associated_with::dephosphorylation of is_associated_with::Cdc25 and is_associated_with::Tau, but protects phosphorylated cyclin D from is_associated_with::ubiquitination and is_associated_with::proteolysis. Recent data also implicate Pin1 as playing an important role in is_associated_with::immune responses, at least in part by increasing the stability of is_associated_with::cytokine is_associated_with::mRNAs by influencing the protein complexes to which they bind. A recent review by Kun Ping Lu attempts to provide a unifying framework for understanding Pin1 function by hypothesising that Pin1 acts as a molecular timer.

Interactions
PIN1 has been shown to interact with is_associated_with::CSNK2A2, is_associated_with::Casein kinase 2, alpha 1, is_associated_with::Wee1-like protein kinase, is_associated_with::FOXO4, is_associated_with::CDC25C, is_associated_with::CDC27,  is_associated_with::MYT1, is_associated_with::PLK1,  is_associated_with::MPHOSPH1, is_associated_with::DAB2, is_associated_with::P53,  is_associated_with::PKMYT1, is_associated_with::C-jun, is_associated_with::SUPT5H, is_associated_with::Mothers against decapentaplegic homolog 3 and is_associated_with::Mothers against decapentaplegic homolog 2. PIN1 has also been shown to interact with endothelial nitric oxide synthase (eNOS).