Biochemical and Biophysical Research Communications
Breakthroughs and ViewsThe RCN family of calcineurin regulators
Section snippets
Discovery of RCNs and initial characterization
RCNs were first identified simultaneously in two disparate fungi, the pathogen Cryptococcus neoformans and the baker’s yeast Saccharomyces cerevisiae. Calcineurin plays a role in pathogenesis of C. neoformans, and to identify potential targets, a yeast two-hybrid screen was performed using C. neoformans calcineurin (calcineurin A) as bait to screen a C. neoformans library. A calcineurin binding protein termed Cbp1 was identified [1]. Calcineurin appeared to dephosphorylate Cbp1, but there was
A general model for RCN stimulation/inhibition of calcineurin
The stimulatory effect of Rcn1 on calcineurin has been examined in a series of genetic experiments in yeast [11]. Rcn1 failed to stimulate calcineurin in a mutant lacking a GSK-3-family protein kinase (Δmck1 mutant). Purified Mck1 kinase phosphorylated Ser 113 in the SP-linker domain of Rcn1 in vitro. Mutagenesis of Ser 113 to Ala abolished phosphorylation in vivo and in vitro and also destroyed the stimulatory activity of Rcn1 on calcineurin signaling but not the inhibitory effect [11]. Thus,
Expression of RCNs
In all fungal and animal species tested (yeast, nematode, mouse, and humans), RCN expression can be strongly induced upon the activation of calcineurin-dependent transcription factors [3], [8], [14]. When this is considered in conjunction with the stimulatory and inhibitory effects on calcineurin, positive and negative feedback loops may operate in vivo. As suggested by computer simulations [11] positive feedback will depend upon adequate levels of the RCN kinases as well as substoichiometric
Future questions
While the details of RCN interactions with calcineurin are being elucidated, many additional questions remain unanswered. What is the structural basis by which RCNs stimulate and inhibit calcineurin signaling? How do RCNs modulate calcineurin signaling in physiological conditions such as Ca2+ waves and oscillations? Do RCNs also function as anchoring subunits for calcineurin and its substrates? Can RCNs integrate signals from protein kinase pathways into the calcineurin signaling pathway? Do
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