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14‐3‐3 proteins mediate inhibitory effects of cAMP on salt‐inducible kinases ( SIK s)
Author(s) -
Sonntag Tim,
Vaughan Joan M.,
Montminy Marc
Publication year - 2018
Publication title -
the febs journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 204
eISSN - 1742-4658
pISSN - 1742-464X
DOI - 10.1111/febs.14351
Subject(s) - phosphorylation , kinase , protein kinase a , chemistry , microbiology and biotechnology , biochemistry , cytoplasm , biology
The salt‐inducible kinase ( SIK ) family regulates cellular gene expression via the phosphorylation of cAMP‐regulated transcriptional coactivators ( CRTC s) and class IIA histone deacetylases, which are sequestered in the cytoplasm by phosphorylation‐dependent 14‐3‐3 interactions. SIK activity toward these substrates is inhibited by increases in cAMP signaling, although the underlying mechanism is unclear. Here, we show that the protein kinase A ( PKA )‐dependent phosphorylation of SIK s inhibits their catalytic activity by inducing 14‐3‐3 protein binding. SIK 1 and SIK 3 contain two functional PKA /14‐3‐3 sites, while SIK 2 has four. In keeping with the dimeric nature of 14‐3‐3s, the presence of multiple binding sites within target proteins dramatically increases binding affinity. As a result, loss of a single 14‐3‐3‐binding site in SIK 1 and SIK 3 abolished 14‐3‐3 association and rendered them insensitive to cAMP . In contrast, mutation of three sites in SIK 2 was necessary to fully block cAMP regulation. Superimposed on the effects of PKA phosphorylation and 14‐3‐3 association, an evolutionary conserved domain in SIK 1 and SIK 2 (the so called RK ‐rich region; 595–624 in hSIK 2) is also required for the inhibition of SIK 2 activity. Collectively, these results point to a dual role for 14‐3‐3 proteins in repressing a family of Ser/Thr kinases as well as their substrates.