title: A novel regulatory mechanism links PLCγ1 to PDK1.
abstract: 3-Phosphoinositide-dependent protein kinase-1 (PDK1) and phospholipase C (PLC)γ1 are two key enzymes in signal transduction that control several intracellular processes. Despite the fact that PLCγ1 has been investigated for several years, the mechanisms of activation of this enzyme are still not completely clear. Similarly, although PDK1 has been mostly investigated for its role in activation of Akt, a crucial enzyme in regulation of several cellular processes, it has become evident recently that the role of PDK1 in physiological and pathological conditions is not limited to Akt activation. Here we demonstrate that PDK1 regulates PLCγ1 activation in a mechanism involving association of the two enzymes and modulation of PLCγ1 tyrosine phosphorylation. We further show that this novel PDK1-PLCγ1 pathway is important for cancer cell invasion. The identification of a PDK1-PLCγ1 pathway reveals the existence of a previously undetected link between two of the most important enzymes in signal transduction. This is likely to have profound consequences for our understanding of several cellular functions that are dependent on phosphoinositides and controlled by PDK1 and PLCγ1.
authors.affiliation: Centre for Diabetes, Blizard Institute, Queen Mary University of London, Barts and The London School of Medicine and Dentistry, London, UK.
authors.forename: Claudio
authors.initials: C
authors.lastname: Raimondi
authors.forename: Anissa
authors.initials: A
authors.lastname: Chikh
authors.forename: Ann P
authors.initials: AP
authors.lastname: Wheeler
authors.forename: Tania
authors.initials: T
authors.lastname: Maffucci
authors.forename: Marco
authors.initials: M
authors.lastname: Falasca
mesh_terms: D064413:3-Phosphoinositide-Dependent Protein Kinases; D002118:Calcium / Q000378:metabolism; D004789:Enzyme Activation; D004815:Epidermal Growth Factor / Q000494:pharmacology; D066246:ErbB Receptors / Q000187:drug effects / Q000378:metabolism; D005434:Flow Cytometry; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006801:Humans; D007191:Indazoles / Q000494:pharmacology; D009361:Neoplasm Invasiveness / Q000235:genetics; D051966:Phospholipase C gamma / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D025941:Protein Interaction Mapping; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014162:Transfection
chemical_list: C555257:GSK 2334470; D007191:Indazoles; D011743:Pyrimidines; D034741:RNA, Small Interfering; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D064413:3-Phosphoinositide-Dependent Protein Kinases; C578562:PDPK1 protein, human; D017346:Protein Serine-Threonine Kinases; D051966:Phospholipase C gamma; D002118:Calcium