Reciprocal regulation of ARPP-16 by PKA and MAST3 kinases provides a cAMP-regulated switch in protein phosphatase 2A inhibition

• DOI: 10.7554/elife.24998
• Publication Date: 2017-06-14T12:00:18Z
• Authors: Veronica Musante; Lu Li; Jean Kanyo; Tukiet T Lam; Christopher M Col...; Shuk Kei Cheng; A Harrison Brody; Paul Greengard; Nicolas Le Novère; Angus C Nairn
• Keywords: Phosphorylation cascade

ARPP-16, ARPP-19, and ENSA are inhibitors of protein phosphatase PP2A. ARPP-19 phosphorylated by Greatwall kinase inhibit PP2A during mitosis. ARPP-16 is expressed in striatal neurons where basal phosphorylation MAST3 inhibits regulates key components signaling. The ARPP-16/19 proteins were discovered as substrates for PKA, but the function PKA unknown. We find that or mutually suppresses ability other to act on ARPP-16. Phosphorylation also acts prevent inhibition MAST3. Moreover, phosphorylates at multiple sites resulting its inhibition. Mathematical modeling highlights role these three regulatory interactions create a switch-like response cAMP. Together, results suggest complex antagonistic interplay between control creates mechanism whereby cAMP mediates disinhibition.