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XB-ART-48421
FEBS J February 1, 2014; 281 (4): 1159-69.

Regulation of α-endosulfine, an inhibitor of protein phosphatase 2A, by multisite phosphorylation.

Mochida S .


Abstract
Progression into M phase requires inhibition of heterotrimeric PP2A containing the regulatory B55 subunit (PP2A-B55) as well as the activation of cyclin-dependent kinase 1 (Cdk1). α-endosulfine (ENSA)/cyclic AMP-regulated 19 kDa phosphoprotein (ARPP-19) family proteins phosphorylated at S67 by Greatwall kinase bind and inhibit PP2A-B55. This study shows that endogenous kinases phosphorylate not only S67 but also two additional sites in ENSA (T28 and S109) with different kinetics at different cell-cycle stages in Xenopus laevis intact cells and cell-free egg extracts. When assayed in vitro, these phosphorylations had qualitatively and/or quantitatively different effects on inhibition of PP2A-B55 by ENSA. Structural analyses revealed that the most-conserved middle region of ENSA containing S67 physically interacts with PP2A-B55 at the interface of the B55 and C subunits, where the catalytic centre of PP2A is located. As non-phosphorylated ENSA has an intrinsic potential for PP2A-B55 inhibition, these three phosphorylations differentially affect physical interaction of the middle region of ENSA with PP2A-B55. These results suggest that the two additional phosphorylation sites together with S67 allow ENSA to function as a ''stepwise tuner'' for PP2A-B55, which may be regulated by multiple cellular signals, rather than a simple ''on/off'' switch.

PubMed ID: 24354984
Article link: FEBS J

Genes referenced: ankrd2 arpp19 cdk1 ensa mastl mink1 ptpa



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