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Dynamic cross‐talk between PI3‐kinase/Akt and Ras/ERK pathways in EGF receptor signaling that can affect drug sensitivity in tumor cells
Author(s) -
Aksamitiene Edita,
Kiyatkin Anatoly,
Hoek Jan B
Publication year - 2010
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.24.1_supplement.715.2
Subject(s) - mapk/erk pathway , wortmannin , pi3k/akt/mtor pathway , protein kinase b , microbiology and biotechnology , signal transduction , blot , kinase , crosstalk , biology , cancer research , chemistry , biochemistry , physics , optics , gene
Cell survival (PI3K/Akt) and mitogenic (Ras/ERK) signaling cascades rarely act as independent parallel pathways, rather they interact at different points and phases of signal propagation, generating positive and negative feedback loops. We explored the patterns of cross‐talk between PI3K and ERK in various normal and cancer cells that were pretreated with wortmannin or U0126 inhibitors prior to stimulation with increasing EGF doses. Time‐courses of total and phosphorylated ERK or Akt expression were detected by Multistrip Western blotting, a novel procedure used for concurrent comparison of signals derived from multiple blots. Quantitative analysis of blots showed that PI3K enhanced and sustained ERK responses, whereas activated ERK suppressed PI3K activity in time‐ and EGF dose‐dependent manner. The differential extent of such bidirectional reciprocal crosstalk could be attributed to diverse recruitment mechanisms of GAB family adaptor proteins, as suggested by immunoblot analyses of subcellular fractions and immunoprecipitates. Dynamic PI3K‐ERK interactions also persist in tumors, making the activation patterns robust to individual perturbations, which can be linked to different drug sensitivity profiles. Nonetheless, combined inhibition of PI3K and ERK activities synergistically decreased tumor cell viability and growth, as measured by AlamarBlue assay. Supported by NIH Grant GM059570