The Tankyrases (TNKS1/PARP5A and TNKS2/PARP5B) are poly (ADP-ribose) polymerases that catalyze the ADP-ribosylation of target proteins. TNKS' are involved in the regulation of Wnt/β-catenin signaling and have been implicated in the pathology of various forms of cancer.
TNKS1 and TNKS2 consist of ankyrin repeats, a SAM domain, and a catalytic ARTD domain. Substrates bind to TNKS through the ankyrin repeats, whereas the SAM domain mediates TNKS multimerization. The ARTD domain catalyzes the conversion of NAD+ to nicotinamide and ADP-ribose, before ADP-ribose is covalently attached to a target substrate or ADP-ribose polymer. TNKS1 has been shown to have autocatalytic activity, whilst GDP-mannose-4,6-dehydratase (GMD) and Fanconi anemia group 2D protein can inhibit TNKS catalytic activity. Phosphorylation of TNKS may also modulate its activity, for example PLK1-mediated phosphorylation may result in TNKS stabilization.
The TNKS' are widely expressed and are involved in a number of physiological processes including, telomere homeostasis, mitotic spindle formation, glucose uptake and Wnt signaling. TNKS regulates Wnt signaling through the modulation of the β-catenin destruction complex, which targets β-catenin for proteasomal degradation. An essential component of the destruction complex is axin1, which is also a TNKS substrate. TNKS-mediated axin1 APD-ribosylation targets axin1 to the proteasome for degradation, decreasing the stability of the destruction complex. This increases free β-catenin levels in the cytoplasm and consequently enhances Wnt/β-catenin signaling and transcription.
TNKS has been implicated in various disease states including, cancer, viral infection and tissue fibrosis. TNKS1 and TNKS2 expression has been reported to be elevated in many types of cancer, with TNKS inhibition being shown to reduce proliferation of colon carcinoma cell lines. TNKS inhibition can also suppress oncogenic Wnt signaling, as inhibition of TNKS stabilizes axin and the destruction complex, therefore attenuating Wnt/β-catenin signaling.View all products for Tankyrase »
Literature for Tankyrase
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