A novel regulatory mechanism links PLC&ggr;1 to PDK1

Summary 3-Phosphoinositide-dependent protein kinase-1 (PDK1) and phospholipase C (PLC)&ggr;1 are two key enzymes in signal transduction that control several intracellular processes. Despite the fact that PLC&ggr;1 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 PLC&ggr;1 activation in a mechanism involving association of the two enzymes and modulation of PLC&ggr;1 tyrosine phosphorylation. We further show that this novel PDK1–PLC&ggr;1 pathway is important for cancer cell invasion. The identification of a PDK1–PLC&ggr;1 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 PLC&ggr;1.

[1]  Z. Kouchi,et al.  Phosphoinositide 3-kinase signaling pathway mediated by p110α regulates invadopodia formation , 2011, The Journal of cell biology.

[2]  M. Falasca,et al.  Targeting PDK1 in cancer. , 2011, Current medicinal chemistry.

[3]  M. Katan,et al.  PLC regulation: emerging pictures for molecular mechanisms. , 2011, Trends in biochemical sciences.

[4]  Ayaz Najafov,et al.  Characterization of GSK2334470, a novel and highly specific inhibitor of PDK1. , 2011, The Biochemical journal.

[5]  M. Falasca,et al.  A Phosphoinositide 3-Kinase/Phospholipase Cgamma1 Pathway Regulates Fibroblast Growth Factor-Induced Capillary Tube Formation , 2009, PloS one.

[6]  Jorma Isola,et al.  3-Phosphoinositide-dependent kinase 1 potentiates upstream lesions on the phosphatidylinositol 3-kinase pathway in breast carcinoma. , 2009, Cancer research.

[7]  Yiling Lu,et al.  AKT-independent signaling downstream of oncogenic PIK3CA mutations in human cancer. , 2009, Cancer cell.

[8]  Y. Liu,et al.  Down-Regulation of 3-Phosphoinositide–Dependent Protein Kinase-1 Levels Inhibits Migration and Experimental Metastasis of Human Breast Cancer Cells , 2009, Molecular Cancer Research.

[9]  S. Iacobelli,et al.  Phospholipase Cgamma1 is required for metastasis development and progression. , 2008, Cancer research.

[10]  Pascale G. Charest,et al.  The regulation of cell motility and chemotaxis by phospholipid signaling , 2008, Journal of Cell Science.

[11]  E. Sahai,et al.  PDK1 regulates cancer cell motility by antagonising inhibition of ROCK1 by RhoE , 2008, Nature Cell Biology.

[12]  A. Wells,et al.  PLCγ contributes to metastasis of in situ-occurring mammary and prostate tumors , 2007, Oncogene.

[13]  M. Falasca,et al.  Phosphoinositide 3-kinase-dependent regulation of phospholipase Cgamma. , 2007, Biochemical Society transactions.

[14]  M. Stone,et al.  Development of a quantitative method to analyse tumour cell invasion in organotypic culture , 2005, The Journal of pathology.

[15]  S. Rhee,et al.  Mechanism of B-Cell Receptor-Induced Phosphorylation and Activation of Phospholipase C-γ2 , 2004, Molecular and Cellular Biology.

[16]  S. Rhee,et al.  Mechanism of tyrosine phosphorylation and activation of phospholipase C-gamma 1. Tyrosine 783 phosphorylation is not sufficient for lipase activation. , 2004, The Journal of biological chemistry.

[17]  J. Grandis,et al.  Phospholipase C-γ1 in tumor progression , 2003, Clinical & Experimental Metastasis.

[18]  Stefano Iacobelli,et al.  The mechanism involved in the regulation of phospholipase Cγ1 activity in cell migration , 2002, Oncogene.

[19]  E. Vigorito,et al.  A Crucial Role for the p110δ Subunit of Phosphatidylinositol 3-Kinase in B Cell Development and Activation , 2002, The Journal of experimental medicine.

[20]  P. Cohen,et al.  The role of 3-phosphoinositide-dependent protein kinase 1 in activating AGC kinases defined in embryonic stem cells , 2000, Current Biology.

[21]  A. Wells,et al.  A Role for Phospholipase C-γ-mediated Signaling in Tumor Cell Invasion , 1999 .

[22]  L. Cantley,et al.  Activation of Phospholipase C-γ by Phosphatidylinositol 3,4,5-Trisphosphate* , 1998, The Journal of Biological Chemistry.

[23]  J. Schlessinger,et al.  Activation of phospholipase Cγ by PI 3‐kinase‐induced PH domain‐mediated membrane targeting , 1998 .

[24]  Mahlon D. Johnson,et al.  Elevated content of the tyrosine kinase substrate phospholipase C-gamma 1 in primary human breast carcinomas. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[25]  D. Alessi,et al.  The nuts and bolts of AGC protein kinases , 2010, Nature Reviews Molecular Cell Biology.

[26]  J. Bayascas,et al.  PDK1: the major transducer of PI 3-kinase actions. , 2010, Current topics in microbiology and immunology.

[27]  Nobutaka Hirokawa,et al.  Disruption of KIF17–Mint1 interaction by CaMKII-dependent phosphorylation: a molecular model of kinesin–cargo release , 2008, Nature Cell Biology.

[28]  M. Falasca,et al.  Phosphoinositide 3-kinase-dependent regulation of phospholipase Cgamma. , 2007, Biochemical Society transactions.

[29]  A. Wells,et al.  PLC gamma contributes to metastasis of in situ-occurring mammary and prostate tumors. , 2007, Oncogene.

[30]  J. Grandis,et al.  Phospholipase C-gamma1 in tumor progression. , 2003, Clinical & experimental metastasis.

[31]  S. Rhee,et al.  Regulation of phosphoinositide-specific phospholipase C. , 2001, Annual review of biochemistry.

[32]  A. Wells,et al.  A role for phospholipase C-gamma-mediated signaling in tumor cell invasion. , 1999, Clinical cancer research : an official journal of the American Association for Cancer Research.

[33]  J. Schlessinger,et al.  Activation of phospholipase C gamma by PI 3-kinase-induced PH domain-mediated membrane targeting. , 1998, The EMBO journal.

[34]  O. Hazeki.  [Phosphoinositide 3-kinase]. , 1997, Tanpakushitsu kakusan koso. Protein, nucleic acid, enzyme.