A Novel Regulatory Mechanism Links PLCγ1 to PDK1

Overview

Journal J Cell Sci

Specialty Cell Biology

Date 2012 Mar 29

PMID 22454520

Citations 24

Authors

Claudio Raimondi

Anissa Chikh

Ann P Wheeler

Tania Maffucci

Marco Falasca

Affiliations

Soon will be listed here.

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.

Citing Articles

TM4SF1 is a molecular facilitator that distributes cargo proteins intracellularly in endothelial cells in support of blood vessel formation.

Lin C, Merley A, Jaminet S J Cell Commun Signal. 2024; 18(2):e12031.

PMID: 38946725 PMC: 11208120. DOI: 10.1002/ccs3.12031.

Associating bovine herpesvirus 1 envelope glycoprotein gD with activated phospho-PLC-γ1(S1248).

Liu C, Yuan W, Yang H, Ni J, Tang L, Zhao H Microbiol Spectr. 2023; :e0196323.

PMID: 37655900 PMC: 10580943. DOI: 10.1128/spectrum.01963-23.

Phosphorylation of LKB1 by PDK1 Inhibits Cell Proliferation and Organ Growth by Decreased Activation of AMPK.

Borkowsky S, Gass M, Alavizargar A, Hanewinkel J, Hallstein I, Nedvetsky P Cells. 2023; 12(5).

PMID: 36899949 PMC: 10000615. DOI: 10.3390/cells12050812.

A Genome-Wide Screen Identifies PDPK1 as a Target to Enhance the Efficacy of MEK1/2 Inhibitors in NRAS Mutant Melanoma.

Cai W, Nguyen M, Wilski N, Purwin T, Vernon M, Tiago M Cancer Res. 2022; 82(14):2625-2639.

PMID: 35657206 PMC: 9298960. DOI: 10.1158/0008-5472.CAN-21-3217.

The Landscape of PDK1 in Breast Cancer.

Wang N, Fu J, Li Z, Jiang N, Chen Y, Peng J Cancers (Basel). 2022; 14(3).

PMID: 35159078 PMC: 8834120. DOI: 10.3390/cancers14030811.

References

Nagashima K, Shumway S, Sathyanarayanan S, Chen A, Dolinski B, Xu Y . Genetic and pharmacological inhibition of PDK1 in cancer cells: characterization of a selective allosteric kinase inhibitor. J Biol Chem. 2010; 286(8):6433-48. PMC: 3057779. DOI: 10.1074/jbc.M110.156463. View

Nystrom M, Thomas G, Stone M, Mackenzie I, Hart I, Marshall J . Development of a quantitative method to analyse tumour cell invasion in organotypic culture. J Pathol. 2005; 205(4):468-75. DOI: 10.1002/path.1716. View

Piccolo E, Innominato P, Mariggio M, Maffucci T, Iacobelli S, Falasca M . The mechanism involved in the regulation of phospholipase Cgamma1 activity in cell migration. Oncogene. 2002; 21(42):6520-9. DOI: 10.1038/sj.onc.1205821. View

Kolsch V, Charest P, Firtel R . The regulation of cell motility and chemotaxis by phospholipid signaling. J Cell Sci. 2008; 121(Pt 5):551-9. PMC: 2671295. DOI: 10.1242/jcs.023333. View

Pinner S, Sahai E . PDK1 regulates cancer cell motility by antagonising inhibition of ROCK1 by RhoE. Nat Cell Biol. 2008; 10(2):127-37. DOI: 10.1038/ncb1675. View

Kassis J, Moellinger J, Lo H, Greenberg N, Kim H, Wells A . A role for phospholipase C-gamma-mediated signaling in tumor cell invasion. Clin Cancer Res. 1999; 5(8):2251-60. View

Clayton E, Bardi G, Bell S, Chantry D, Downes C, Gray A . A crucial role for the p110delta subunit of phosphatidylinositol 3-kinase in B cell development and activation. J Exp Med. 2002; 196(6):753-63. PMC: 2194055. DOI: 10.1084/jem.20020805. View

Bayascas J . PDK1: the major transducer of PI 3-kinase actions. Curr Top Microbiol Immunol. 2010; 346:9-29. DOI: 10.1007/82_2010_43. View

Maurer M, Su T, Saal L, Koujak S, Hopkins B, Barkley C . 3-Phosphoinositide-dependent kinase 1 potentiates upstream lesions on the phosphatidylinositol 3-kinase pathway in breast carcinoma. Cancer Res. 2009; 69(15):6299-306. PMC: 2727605. DOI: 10.1158/0008-5472.CAN-09-0820. View

10.

Maffucci T, Raimondi C, Abu-Hayyeh S, Dominguez V, Sala G, Zachary I . A phosphoinositide 3-kinase/phospholipase Cgamma1 pathway regulates fibroblast growth factor-induced capillary tube formation. PLoS One. 2009; 4(12):e8285. PMC: 2788267. DOI: 10.1371/journal.pone.0008285. View

11.

Najafov A, Sommer E, Axten J, DeYoung M, Alessi D . Characterization of GSK2334470, a novel and highly specific inhibitor of PDK1. Biochem J. 2010; 433(2):357-69. DOI: 10.1042/BJ20101732. View

12.

Williams M, Arthur J, Balendran A, van der Kaay J, Poli V, Cohen P . The role of 3-phosphoinositide-dependent protein kinase 1 in activating AGC kinases defined in embryonic stem cells. Curr Biol. 2000; 10(8):439-48. DOI: 10.1016/s0960-9822(00)00441-3. View

13.

Raimondi C, Falasca M . Targeting PDK1 in cancer. Curr Med Chem. 2011; 18(18):2763-9. DOI: 10.2174/092986711796011238. View

14.

Bae Y, Cantley L, Chen C, Kim S, Kwon K, Rhee S . Activation of phospholipase C-gamma by phosphatidylinositol 3,4,5-trisphosphate. J Biol Chem. 1998; 273(8):4465-9. DOI: 10.1074/jbc.273.8.4465. View

15.

Pearce L, Komander D, Alessi D . The nuts and bolts of AGC protein kinases. Nat Rev Mol Cell Biol. 2009; 11(1):9-22. DOI: 10.1038/nrm2822. View

16.

Vasudevan K, Barbie D, Davies M, Rabinovsky R, McNear C, Kim J . AKT-independent signaling downstream of oncogenic PIK3CA mutations in human cancer. Cancer Cell. 2009; 16(1):21-32. PMC: 2752826. DOI: 10.1016/j.ccr.2009.04.012. View

17.

Falasca M, Logan S, Lehto V, Baccante G, Lemmon M, Schlessinger J . Activation of phospholipase C gamma by PI 3-kinase-induced PH domain-mediated membrane targeting. EMBO J. 1998; 17(2):414-22. PMC: 1170392. DOI: 10.1093/emboj/17.2.414. View

18.

Yamaguchi H, Yoshida S, Muroi E, Yoshida N, Kawamura M, Kouchi Z . Phosphoinositide 3-kinase signaling pathway mediated by p110α regulates invadopodia formation. J Cell Biol. 2011; 193(7):1275-88. PMC: 3216328. DOI: 10.1083/jcb.201009126. View

19.

Liu Y, Wang J, Wu M, Wan W, Sun R, Yang D . Down-regulation of 3-phosphoinositide-dependent protein kinase-1 levels inhibits migration and experimental metastasis of human breast cancer cells. Mol Cancer Res. 2009; 7(6):944-54. DOI: 10.1158/1541-7786.MCR-08-0368. View

20.

Arteaga C, Johnson M, Todderud G, Coffey R, Carpenter G, Page D . Elevated content of the tyrosine kinase substrate phospholipase C-gamma 1 in primary human breast carcinomas. Proc Natl Acad Sci U S A. 1991; 88(23):10435-9. PMC: 52943. DOI: 10.1073/pnas.88.23.10435. View