Reciprocal regulation of ARPP-16 by PKA and MAST3 kinases provides a cAMP-regulated switch in protein phosphatase 2A inhibition
0303 health sciences
phosphatase PP2A
QH301-705.5
Science
Q
R
neurons
Protein Serine-Threonine Kinases
Phosphoproteins
Cyclic AMP-Dependent Protein Kinases
purified proteins
computational model
03 medical and health sciences
HEK293 Cells
Gene Expression Regulation
hek293 cell line
Cyclic AMP
Medicine
Humans
Protein Phosphatase 2
Biology (General)
Microtubule-Associated Proteins
Computational and Systems Biology
DOI:
10.7554/elife.24998
Publication Date:
2017-06-14T12:00:18Z
AUTHORS (10)
ABSTRACT
ARPP-16, ARPP-19, and ENSA are inhibitors of protein phosphatase PP2A. ARPP-19 and ENSA phosphorylated by Greatwall kinase inhibit PP2A during mitosis. ARPP-16 is expressed in striatal neurons where basal phosphorylation by MAST3 kinase inhibits PP2A and regulates key components of striatal signaling. The ARPP-16/19 proteins were discovered as substrates for PKA, but the function of PKA phosphorylation is unknown. We find that phosphorylation by PKA or MAST3 mutually suppresses the ability of the other kinase to act on ARPP-16. Phosphorylation by PKA also acts to prevent inhibition of PP2A by ARPP-16 phosphorylated by MAST3. Moreover, PKA phosphorylates MAST3 at multiple sites resulting in its inhibition. Mathematical modeling highlights the role of these three regulatory interactions to create a switch-like response to cAMP. Together, the results suggest a complex antagonistic interplay between the control of ARPP-16 by MAST3 and PKA that creates a mechanism whereby cAMP mediates PP2A disinhibition.
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