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Investigating PEA‐15's ability to regulate ERK1/2 MAP Kinase activation
Author(s) -
Haling Jacob,
Ginsberg Mark
Publication year - 2009
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.23.1_supplement.710.9
Subject(s) - mapk7 , map kinase kinase kinase , mitogen activated protein kinase , grb2 , microbiology and biotechnology , mapk14 , mitogen activated protein kinase kinase , signal transduction , receptor tyrosine kinase , phosphorylation , kinase , mapk/erk pathway , biology , cancer research , protein kinase a
PEA‐15 is a highly‐conserved protein expressed in many vascular cells. Increased PEA‐15 expression leads to dramatically increased activation of ERK1/2 MAP kinase, a key regulator of cell proliferation and gene expression, due to activation of Ras and MEK, the upstream components of the MAP kinase pathway. Here we show that PEA‐15 mediates activation of this pathway by interrupting a key negative feedback loop in the MAP kinase pathway. FRS2 is a central adaptor for receptor tyrosine kinase activation of Ras signaling; ERK1/2 phosphorylates FRS2 to inhibit Ras activation. We report that PEA‐15 binds to ERK1/2, thereby preventing their membrane recruitment. In consequence, ERK1/2 are unable to phosphorylate FRS2, thereby prolonging its capacity to recruit Grb2‐Sos and thereby activate Ras. Genetic deletion of FRS2 blocks the capacity of PEA‐15 to activate the MAP kinase pathway and reconstitution with phosphorylation mutants of FRS2 abrogates the ability of PEA‐15 to regulate ERK1/2 activation. Thus, PEA‐15 serves as a modulator of the classical MAP kinase pathway by preventing the ERK1/2‐dependent phosphorylation of FRS2.