Platelet-derived growth factor-induced Akt phosphorylation requires mTOR/Rictor and phospholipase C-γ1, whereas S6 phosphorylation depends on mTOR/Raptor and phospholipase D

Platelet-derived growth factor (PDGF) stimulates proliferation, migration and survival of mesenchymal cells and plays a pivotal role during embryonic development and wound healing [1]. The biologically active form of PDGF consists of disulphide-linked dimers, PDGF-AA, -AB, -BB, -CC and –DD, which bind to two structurally similar tyrosine kinase receptors, i.e. PDGFRα and PDGFRβ [2,3]. PDGFRα binds all PDGF chains except PDGF-D, whereas PDGFRβ interacts only with PDGF B- and D-chains. The binding of the bivalent ligand induces dimerization and activation of PDGFRs, leading to autophosphorylation of tyrosine residues in the intracellular region [2]. Thereby, several signal transduction pathways are initiated, including phosphatidylinositol 3-kinase (PI3K), the Src tyrosine kinase, phospholipase Cγ (PLC), and several mitogen-activated protein (MAP) kinase cascades.mTOR is the mammalian ortholog of the yeast serine/threonine kinase TOR which is involved in the regulation of various cellular functions, such as initiation of translation, cell growth and proliferation, ribosome biogenesis, transcription and cytoskeletal reorganization [4]. Dysregulation of mTOR signaling is frequently seen in cancer and has attracted attention as a therapeutic target [5,6]. mTOR is functional in two distinct complexes, namely mTORC1 and mTORC2 [7]. mTORC1 activity is controlled by the G-protein Rheb; Rheb-GTP promotes mTORC1 activity and the tuberous sclerosis complex 1/2 (TSC1/2) acts as a GTPase activating protein for Rheb, consequently inhibiting mTORC1 activity [8]. Generally, mTORC1 is described as being activated by growth factors through Akt-mediated phosphorylation which inactivates the TSC1/2 complex [8-10]. In addition, the TSC1/2 complex can also be phosphorylated and inhibited by AMPK, thus allowing the cellular energy status to impact mTORC1 activity [11]. mTORC1 is a rapamycin-sensitive complex, and includes the proteins Raptor (regulatory-associated protein of mTOR), mLST8,