Inhibition of CREB phosphorylation by conjugates of adenosine analogues and arginine-rich peptides, inhibitors of PKA catalytic subunit.

Bisubstrate inhibitors of protein kinases associate simultaneously with two substrate-binding sites of the kinase and thus potentially possess better inhibitory potency and selectivity than inhibitors binding to only the conserved ATP-site of the kinase. We have previously used conjugates of adenosine analogues and arginine-rich peptides (ARCs) to develop proteolytically stable cell plasma membrane-permeable bisubstrate inhibitors whose biochemical affinities towards several basophilic protein kinases of the AGC group are in the picomolar range. The potency of bisubstrate inhibitors to affect the phosphorylation of proteins in living cells has been described in a limited number of publications. In this study, the effect of ARCs on the protein kinase A (PKA)-catalysed cAMP response element-binding protein (CREB) phosphorylation pathway was studied in living mammalian cells. Our results demonstrate that at low micromolar extracellular concentration N-myristoylated ARCs are capable of reducing the activity of transcription factor CREB through inhibition of PKA. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Citation

Marie Kriisa, Hedi Sinijärv, Angela Vaasa, Erki Enkvist, Sergiy Kostenko, Ugo Moens, Asko Uri. Inhibition of CREB phosphorylation by conjugates of adenosine analogues and arginine-rich peptides, inhibitors of PKA catalytic subunit. Chembiochem : a European journal of chemical biology. 2015 Jan 19;16(2):312-9

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PMID: 25487811

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