Protein kinase A-mediated phosphorylation of the RASSF1A tumour suppressor at Serine 203 and regulation of RASSF1A function

European Journal of Cancer : Official Journal for European Organization for Research and Treatment of Cancer (EORTC) [and] European Association for Cancer Research (EACR)
Antje M RichterR Dammann

Abstract

Epigenetic inactivation of the Ras-Association Domain Family 1A (RASSF1A) gene is one of the most frequent alterations detected in cancer. The tumour suppressor function of RASSF1A contributes to cell cycle progression, microtubule stabilisation and apoptotic signalling. Here we investigated the putative phosphorylation sites of RASSF1A and the functional consequences. RASSF1A is mainly phosphorylated at Serine 203 within its Ras association domain. Phosphorylation at this site is accomplished by protein kinase A (PKA) and is reduced and elevated by PKA-specific inhibitors and activators, respectively. Functionally, an alanine substitution of Serine 203 (S203A) slightly affected the microtubule stability mediated by RASSF1A (p<0.05). Interestingly, the inhibition of PKA and the S203A substitution of RASSF1A resulted in a reduced rate of apoptotic cells induced by RASSF1A. Moreover, RASSF1A-mediated upregulation of p21 and BAX was observed. This induction was reduced when the S203A substitution was present or when PKA activity was inhibited. In summary our data show that RASSF1A is phosphorylated by PKA and this phosphorylation may affect apoptotic signalling of RASSF1A. Thus epigenetic silencing of RASSF1A may counteract its pr...Continue Reading

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Citations

Nov 25, 2011·The Journal of Investigative Dermatology·Peter HelmboldReinhard H Dammann
May 12, 2012·Molecular Biology International·Claudia DittfeldReinhard H Dammann
Jan 22, 2018·Cellular and Molecular Life Sciences : CMLS·Hiroaki IwasaYutaka Hata
Dec 6, 2019·Cell Death & Disease·Fatéméh DuboisGuénaëlle Levallet
Oct 17, 2014·World Journal of Gastroenterology : WJG·Jing ShiPeng Hou
Jan 23, 2020·Cancers·Lucía García-GutiérrezDavid Matallanas
May 16, 2019·Nature Communications·Swati DabralSoni S Pullamsetti

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