Differential activation of ERKs to focal adhesions by PKC ε is required for PMA-induced adhesion and migration of human glioma cells

Protein kinase C (PKC) is a family of serine/threonine kinases involved in the transduction of a variety of signals. There is increasing evidence to indicate that specific PKC isoforms are involved in the regulation of distinct cellular processes. In glioma cells, PKC α was found to be a critical regulator of proliferation and cell cycle progression, while PKC ε was found to regulate adhesion and migration. Herein, we report that specific PKC isoforms are able to differentially activate extracellular-signal regulated kinase (ERK) in distinct cellular locations: while PKC α induces the activation of nuclear ERK, PKC ε induces the activation of ERK at focal adhesions. Inhibition of the ERK pathway completely abolished the PKC-induced integrin-mediated adhesion and migration. Thus, we present the first evidence that PKC ε is able to activate ERK at focal adhesions to mediate glioma cell adhesion and motility, providing a molecular mechanism to explain the different biological functions of PKC α and ε in glioma cells.

[1]  M. Nagasawa,et al.  12-O-Tetradecanoylphorbol-13acetate Activates the Ras/ Extracellular Signal-regulated Kinase (ERK) Signaling Pathway Upstream of SOS Involving Serine Phosphorylation of Shc in NIH3T3 Cells* , 1997, The Journal of Biological Chemistry.

[2]  S. Winder,et al.  Active ERK/MAP kinase is targeted to newly forming cell–matrix adhesions by integrin engagement and v‐Src , 2000, The EMBO journal.

[3]  R. Juliano,et al.  Distinct Mechanisms Mediate the Initial and Sustained Phases of Integrin-mediated Activation of the Raf/MEK/Mitogen-activated Protein Kinase Cascade* , 1998, The Journal of Biological Chemistry.

[4]  S. Rosenfeld,et al.  Glioma migration can be blocked by nontoxic inhibitors of myosin II. , 1999, Cancer research.

[5]  B. Monia,et al.  PKC-ε Is Required for Mechano-sensitive Activation of ERK1/2 in Endothelial Cells* , 1997, The Journal of Biological Chemistry.

[6]  R. Law,et al.  Inhibition of human malignant glioma cell motility and invasion in vitro by hypericin, a potent protein kinase C inhibitor. , 1997, Cancer letters.

[7]  A. Newton,et al.  Regulation of protein kinase C. , 1997, Current opinion in cell biology.

[8]  M. Berens,et al.  "...those left behind." Biology and oncology of invasive glioma cells. , 1999, Neoplasia.

[9]  Jonathan A. Cooper,et al.  Src family kinases are required for integrin but not PDGFR signal transduction , 1999, The EMBO journal.

[10]  V. Wee Yong,et al.  Involvement of p21Waf1/Cip1 in Protein Kinase C Alpha-Induced Cell Cycle Progression , 2000, Molecular and Cellular Biology.

[11]  E. Holland,et al.  Glioblastoma multiforme: the terminator. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[12]  David A. Cheresh,et al.  Regulation of Cell Motility by Mitogen-activated Protein Kinase , 1997, The Journal of cell biology.

[13]  H. Schaeffer,et al.  Mitogen-Activated Protein Kinases: Specific Messages from Ubiquitous Messengers , 1999, Molecular and Cellular Biology.

[14]  A. Satoh,et al.  Decreased activity of xanthine dehydrogenase and serum uric acid in rats fed partially hydrogenated fish oil , 1993 .

[15]  G. G. Stokes.  "J." , 1890, The New Yale Book of Quotations.

[16]  R. Juliano,et al.  Integrins Regulate the Linkage between Upstream and Downstream Events in G Protein-coupled Receptor Signaling to Mitogen-activated Protein Kinase* , 2000, The Journal of Biological Chemistry.

[17]  G L Johnson,et al.  Organization and regulation of mitogen-activated protein kinase signaling pathways. , 1999, Current opinion in cell biology.

[18]  C. Marshall,et al.  Activation of the Mitogen-Activated Protein Kinase/Extracellular Signal-Regulated Kinase Pathway by Conventional, Novel, and Atypical Protein Kinase C Isotypes , 1998, Molecular and Cellular Biology.

[19]  A. Bhushan,et al.  Inhibition of phospholipase C-gamma1 activation blocks glioma cell motility and invasion of fetal rat brain aggregates. , 1999, Neurosurgery.

[20]  J. Brugge,et al.  Protein Kinase C Regulates Integrin-induced Activation of the Extracellular Regulated Kinase Pathway Upstream of Shc* , 1999, The Journal of Biological Chemistry.

[21]  E. Bongcam-Rudloff,et al.  Cell scattering and migration induced by autocrine transforming growth factor alpha in human glioma cells in vitro. , 1997, Cancer research.

[22]  Jeffrey C. Allen,et al.  Migration of Brain Tumor Cells on Extracellular Matrix Proteins in Vitro Correlates with Tumor Type and Grade and Involves αv and β1 Integrins , 1996 .

[23]  S. L. Gonias,et al.  Myosin Light Chain Kinase Functions Downstream of Ras/ERK to Promote Migration of Urokinase-Type Plasminogen Activator-Stimulated Cells in an Integrin-Selective Manner , 1999, The Journal of cell biology.