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AT THE CROSSROADS BETWEEN TYR AND SER/THR SIGNALING: A NEW PARADIGM IN THE REGULATION OF PP2A BY SRC KINASE
Author(s) -
Sontag Estelle,
Sontag JeanMarie,
Gomez Rey J,
Hoffman Alexander,
Taleski Goce,
Mazalouskas Matthew D,
Hanks Steven K,
Frohner Ingrid,
Ogris Egon,
Wadzinski Brian E
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.771.2
Subject(s) - protein phosphatase 2 , phosphorylation , proto oncogene tyrosine protein kinase src , signal transduction , kinase , microbiology and biotechnology , phosphatase , cancer research , biology
The major enzyme, Ser/Thr protein phosphatase 2A (PP2A), is a key regulator of cellular signal transduction pathways. While PP2A dysfunction has been linked to human cancer and neurodegenerative disorders such as Alzheimer disease (AD), PP2A regulation remains relatively poorly understood, precluding the development of effective PP2A‐centric therapies. It has been reported more than two decades ago that the PP2A catalytic subunit (PP2Ac) is inactivated in vitro by phosphorylation at Tyr307 by tyrosine kinases such as v‐Src. Numerous studies relying on the use of commercial “PP2Ac pY307 antibodies” have subsequently linked enhanced phosphorylation of PP2A at Tyr307 with pathological cascades in cancer and AD. In contrast, we present here novel evidence in multiple cell types showing that PP2Ac is not phosphorylated at Tyr307. Rather, we uncover a novel mechanism of regulation of PP2A by Src that affects PP2A substrate specificity. Using specific PP2A mutants, we show that Src‐dependent PP2A deregulation can affect the phosphorylation of tau at Ser/Thr epitopes, a pathological hallmark of AD. It also influences the activation of ERK, a major growth regulatory kinase upregulated in many cancers. Our findings unveil a novel functional Src kinase/PP2A signalling module that positions these enzymes at the interface between Tyr and Ser/Thr signaling pathways. We propose that dysregulation of this Src‐PP2A signaling node may contribute to cancer and AD. Support or Funding Information Supported by NHMRC grant APP1002744 and a grant from the Hunter Medical Research Institute, Australia (ES and JMS), and NIH grants GM051366 and DK070787 (BEW), and T32 GM08554 (MDM).