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Genetic depletion of the phosphatase PHLPP1 upregulates receptor tyrosine kinase signaling
Author(s) -
Reyes Gloria Ximena,
Newton Alexandra
Publication year - 2012
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.26.1_supplement.761.14
Subject(s) - protein kinase b , mapk/erk pathway , receptor tyrosine kinase , microbiology and biotechnology , pi3k/akt/mtor pathway , signal transduction , biology , protein tyrosine phosphatase , tyrosine kinase , phosphatase , phosphorylation , chemistry
The PH‐domain leucine rich repeat protein phosphatase PHLPP1 is a Ser/Thr phosphatase that negatively regulates Akt signaling. This pathway controls many cellular processes; loss of PHLPP leads to hyperactivation of Akt and an imbalance in cell homeostasis, triggering many diseases. Using cells derived from a phlpp1−/− mouse, we show that PHLPP1 suppresses the amplitude of the ERK pathway through an Akt‐independent mechanism. phlpp1−/− cells have increased receptor tyrosine kinase levels leading to augmented activation of downstream signaling. In these cells, the effects on ERK are due to an increased rate of receptor biosynthesis, not defective receptor degradation. Neither pharmacological inhibition of the PI3K‐Akt pathway, nor the MEK‐Erk pathway affects receptor levels, indicating that the PHLPP1 target is not Akt nor ERK. Furthermore, the catalytic and leucine rich repeat regions are critical to regulate receptor levels in normal cells. To find the mechanism controlling receptor levels, we performed pharmacological and PCR arrays to dissect the components responsible for this phenotype in phlpp1−/− cells. Our data indicate that general transcriptional machinery rather than only one transcriptional factor are involved. These data unveil an additional function of PHLPP1 in suppressing receptor tyrosine kinase signaling in cells by a transcriptional mechanism. This work was funded by NIH GM067946.