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PLD2 activates AKT. Evidence of an AKT‐PLD2 short loop feedback mechanism autoregulating DNA synthesis
Author(s) -
GomezCambronero Julian,
Di Fulvio Mauricio,
Frondorf Kathleen,
Henkels Karen
Publication year - 2007
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.21.5.a621-a
Subject(s) - protein kinase b , phosphorylation , pi3k/akt/mtor pathway , pld2 , microbiology and biotechnology , chemistry , biology , cancer research , signal transduction , biochemistry , phospholipid , phosphatidic acid , membrane
Phospholipase D (PLD) is emerging as a regulator of cell proliferation, transformation, tumor progression and survival. However, as most mechanistic details are still unknown, we investigated here if the PLD2 isoform would signal through the PI3K/AKT pathway in the absence of any extracellular stimuli. Overexpression of PLD2 in COS7 cells resulted in increased basal phosphorylation of AKT in residues T308 and S473 in a PI3K‐dependent manner. We identified PLD2 residue T175 as a substrate for PLD2‐activated AKT. If a PLD2 mutant (PLD2 Y179F), whose expression correlated with DNA synthesis, is further mutated in residue T175, its overexpression in cells results in a lack of AKT‐mediated phosphorylation. Further, this new mutant could not induce DNA synthesis, suggesting that T175 is, indeed, a key effector of AKT. Moreover, PLD2 Y179F‐increased DNA synthesis, G0/G1 phase transition markers expression and p42/44ERK phosphorylation were dependent on basal PI3K activity. However, the MEK inhibitor PD98059 did not change the phosphorylation state of AKT in response to Y179F overexpression. These results suggest for the first time a dual AKT‐PLD2 regulatory loop that affects DNA synthesis and is independent of cell survival or extracellular stimuli.