PLD1 Regulates mTOR Signaling and Mediates Cdc42 Activation of S6K1

Abstract

Our observations reveal the involvement of PLD1 in mTOR signaling and cell size control, and provide a molecular mechanism for Cdc42 activation of S6K1. A new cascade is proposed to connect mitogenic signals to mTOR through Cdc42, PLD1, and PA.

Stress and mTORture signaling

“…A recent study showed that mTOR activation by mechanical stimulation of skeletal muscle involved phospholipase D producing the lipid messenger phosphatidic acid (PA) . PA binds the FRB domain of TOR and activates S6K1 activity (Fang et al, 2003). S6K activity is also regulated by other exercise-induced stress conditions such as cyclic strain imposed on smooth muscle cells (SMC).…”

mTOR signaling: PLD takes center stage

“…25,[31][32][33] Overexpression of either PLD1 or PLD2 activates mTORC1 signaling in various types of cells (reviewed in ref. 34), whereas PLD knockdown blocks mitogenic activation of mTORC1 signaling.…”

“…34), whereas PLD knockdown blocks mitogenic activation of mTORC1 signaling. 32,35,36 The small G protein Cdc42 had long been known as an activator of S6K1 with an exact mechanism yet to be determined, 37 and now PLD1 has been revealed as a molecular link between Cdc42 and mTORC1. 32 In addition to PLD, two other PA-producing enzymes-lysophosphatidic acid acyltransferase (LPAAT) and diacylglycerol kinase (DGK)-have also been shown to regulate mTOR signaling through PA, 38,39 further validating the link between PA and mTOR.…”

Mutation of Y179 on phospholipase D2 (PLD2) upregulates DNA synthesis in a PI3K-and Akt-dependent manner

“…PLD plays a role in growth factor-induced cellular proliferation [3][4][5][6] and facilitates oncogenic transformation [7][8][9][10]. Endogenous PLD activity is significantly increased in several types of cancers [11][12][13][14][15], as well as in cell lines transformed with oncogenes [4,5,8,10,[16][17][18][19]. PLD may participate in the activation of p42/44 ERK via Raf-1 translocation to the plasma membrane [20][21][22][23], as well as in the survival signaling mediated by PI3K/AKT activation [24].…”

“…Bad, caspase 9, Mdm2) [29][30][31][32]. Interestingly, most of these effectors can also be regulated by PLD [16,21,22,25,[33][34][35][36]. Furthermore, AKT and bacterial PLD interact [37] and PLD plays a critical role in the PI3K-dependent activation of AKT [38][39][40][41][42].…”