RCAN1 (DSCR1 or Adapt78) stimulates expression of GSK-3beta.
The RCAN1 protein (previously called calcipressin 1 or MCIP1) binds to calcineurin, a serine/threonine phosphatase (PP2B), and inhibits its activity. Here we demonstrate that regulated overexpression of an RCAN1 transgene (this gene was previously called DSCR1 or Adapt78) also stimulates expression of the GSK-3beta kinase, which can antagonize the action of calcineurin. We also show that GSK-3beta is regulated by RCAN1 at a post-transcriptional level. In humans, high RCAN1 expression is found in the brain, where at least two mRNA isoforms have been reported. Therefore, we further investigated expression of the various RCAN1 isoforms, resulting from differential splicing and alternative promotors in human brain. We detected at least three distinct RCAN1s: RCAN1-1 Short at 31 kDa (RCAN1-1S), RCAN1-1 Long at 38 kDa (RCAN1-1 L), and RCAN1-4. Furthermore, the levels of RCAN1-1S, but not RCAN1-1 L or RCAN1-4 correlated with the levels of GSK-3beta. This suggests that RCAN1-1S might induce production of GSK-3beta in vivo. While RCAN1s can regulate calcineurin and GSK-3beta, it has also been shown that calcineurin and GSK-3beta can regulate RCAN1s. Here we propose a new model (incorporating all these findings) in which cells maintain an equilibrium between RCAN1s, calcineurin, and GSK-3beta.
Ermak
Gennady
G
Ethel Percy Andrus Gerontology Center, The University of Southern California, Los Angeles, CA 90089-0191, USA. kelvin@usc.edu
Harris
Cathryn D
CD
Battocchio
Denis
D
Davies
Kelvin J A
KJ
D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism; D019703:Calcineurin / Q000187:drug effects; D002460:Cell Line; D002478:Cells, Cultured; D004268:DNA-Binding Proteins; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism* / Q000494:pharmacology; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000502:physiology*; D009124:Muscle Proteins / Q000235:genetics / Q000502:physiology*; D016716:PC12 Cells; D020033:Protein Isoforms / Q000145:classification / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation
D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D009124:Muscle Proteins; D020033:Protein Isoforms; C108612:RCAN1 protein, human; D011994:Recombinant Proteins; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D038362:Glycogen Synthase Kinase 3; D019703:Calcineurin