Milea Timbergen

38 Stabilization of DTF occurred in four patients which received IFN-ɑ± tretinoin 117 . Despite these encouraging results, no prospective clinical trials in DTF have been carried out yet. The PI3 kinase/AKT and mTOR signalling pathways in des- moid-type fibromatosis The PI3 kinase/ AKT and mTOR signalling pathways The phosphoinositide 3 (PI3) kinase signalling pathway plays a critical role in various cellular processes like cell growth, survival, proliferation, metabolism and differentiation (reviewed by Engelmann et al. 118 ). The pathway is activated by plasma membrane proteins including receptor tyrosine kinases, integrins, B- and T-cell receptors, cytokine receptors and GPCRs and entails the formation of membrane-bound phosphatidylinositol-3,3,5- triphosphate (PIP3) by the enzyme PI3 kinase. Proteins that harbour a pleckstrin-homology (PH) domain like AKT (protein kinase B or PKB) and PDK1 bind to the 3-phosphoinositides on the membrane. Subsequent phosphorylation of AKT at the Thr308 and Ser473 residues, by PDK1 and mTORC2, respectively, fully activates its serine/threonine kinase potential. AKT consequently phosphorylates many downstream substrates, thereby regulating various cellular functions (reviewed by Hers et al. 119 ). Importantly, AKT also leads to downstream activation of the mTOR complex 1 (mTORC1) pathway by phosphorylation of its negative regulators TSC2 and PRAS40. Activation of this complex provides a growth advantage for cells, as mTORC1 is critical for cell maintenance by sensing nutritional and environmental cues and responding by inhibiting autophagy and regulating translation thereby stimulating cell growth and proliferation (reviewed by Hers et al. 119 . and Dowling et al. 120 ). The PI3 kinase/AKT and mTOR signalling pathways in cancer Dysregulation of the PI3 kinase/AKT signalling pathway is frequently encountered in cancers and facilitates tumorigenesis. Over-activation of AKT may be caused by the presence of gain-of-function mutations in PI3K subunits, or loss-of- function mutations in Phosphatase and Tensin homolog deleted from chromosome ten (PTEN) or PTEN expression loss. PTEN, a tumour suppressor is a lipid phosphatase, negatively regulating AKT by dephosphorylation of PIP3. Alternatively, overexpression or activating mutations in tyrosine kinase receptors and their ligands, as well as the interaction of Ras with PI3K, can excite AKT activity (reviewed by Brugge et al. 121 and Keniry and Parsons 122 ). 2