HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 279, Issue 15, 14551-14560, April 9, 2004

This Article Full Text Full Text (PDF) All Versions of this Article: 279/15/14551    most recent M311981200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Iwabu, A. Articles by Wells, A. Search for Related Content PubMed PubMed Citation Articles by Iwabu, A. Articles by Wells, A. Social Bookmarking                      What's this?

Epidermal Growth Factor Induces Fibroblast Contractility and Motility via a Protein Kinase C -dependent Pathway^*

Akihiro Iwabu, Kirsty Smith, Fred D. Allen¶, Douglas A. Lauffenburger, and Alan Wells||

From the Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, the Biological Engineering Division, Department of Biology and Center for Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, and the ^¶School of Biomedical Engineering, Drexel University, Philadelphia, Pennsylvania 19104

Myosin-based cell contractile force is considered to be a critical process in cell motility. However, for epidermal growth factor (EGF)-induced fibroblast migration, molecular links between EGF receptor (EGFR) activation and force generation have not been clarified. Herein, we demonstrate that EGF stimulation increases myosin light chain (MLC) phosphorylation, a marker for contractile force, concomitant with protein kinase C (PKC) activity in mouse fibroblasts expressing human EGFR constructs. Interestingly, PKC is the most strongly phosphorylated isoform, and the preferential PKC inhibitor rottlerin largely prevented EGF-induced phosphorylation of PKC substrates and MARCKS. The pathway through which EGFR activates PKC is suggested by the fact that the MEK-1 inhibitor U0126 and the phosphatidylinositol 3-kinase inhibitor LY294002 had no effect on PKC activation, whereas lack of PLC signaling resulted in delayed PKC activation. EGF-enhanced MLC phosphorylation was prevented by a specific MLC kinase inhibitor ML-7 and the PKC inhibitors chelerythrine chloride and rottlerin. Further indicating that PKC is required, a dominant-negative PKC construct or RNAi-mediated PKC depletion also prevented MLC phosphorylation. In the absence of PLC signaling, MLC phosphorylation and cell force generation were delayed similarly to PKC activation. All of the interventions that blocked PKC activation or MLC phosphorylation abrogated EGF-induced cell contractile force generation and motility. Our results suggest that PKC activation is responsible for a major part of EGF-induced fibroblast contractile force generation. Hence, we identify here a new pathway helping to govern cell motility, with PLC signaling playing a role in activation of PKC to promote the acute phase of EGF-induced MLC activation.

Received for publication, October 31, 2003 , and in revised form, January 26, 2004.

^* These studies were supported by grants from the National Institute for General Medical Sciences and National Cancer Institute at the National Institutes of Health. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^|| To whom correspondence should be addressed: Dept. of Pathology, S713 Scaife Hall, University of Pittsburgh, Pittsburgh, PA 15261. Tel.: 412-647-7813; Fax: 412-647-8567; E-mail: wellsa{at}msx.upmc.edu.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				S.-K. Shields, C. Nicola, and C. Chakraborty Rho Guanosine 5'-Triphosphatases Differentially Regulate Insulin-Like Growth Factor I (IGF-I) Receptor-Dependent and -Independent Actions of IGF-II on Human Trophoblast Migration Endocrinology, October 1, 2007; 148(10): 4906 - 4917. [Abstract] [Full Text] [PDF]

				C.-L. Chen, Y.-T. Hsieh, and H.-C. Chen Phosphorylation of adducin by protein kinase C{delta} promotes cell motility J. Cell Sci., April 1, 2007; 120(7): 1157 - 1167. [Abstract] [Full Text] [PDF]

				G. Pula, K. Schuh, K. Nakayama, K. I. Nakayama, U. Walter, and A. W. Poole PKC{delta} regulates collagen-induced platelet aggregation through inhibition of VASP-mediated filopodia formation Blood, December 15, 2006; 108(13): 4035 - 4044. [Abstract] [Full Text] [PDF]

				G. Vlotides, M. Cruz-Soto, T. Rubinek, T. Eigler, C. J. Auernhammer, and S. Melmed Mechanisms for Growth Factor-Induced Pituitary Tumor Transforming Gene-1 Expression in Pituitary Folliculostellate TtT/GF Cells Mol. Endocrinol., December 1, 2006; 20(12): 3321 - 3335. [Abstract] [Full Text] [PDF]

				F. Renault-Mihara, F. Beuvon, X. Iturrioz, B. Canton, S. De Bouard, N. Leonard, S. Mouhamad, A. Sharif, J. W. Ramos, M.-P. Junier, et al. Phosphoprotein Enriched in Astrocytes-15 kDa Expression Inhibits Astrocyte Migration by a Protein Kinase C{delta}-dependent Mechanism Mol. Biol. Cell, December 1, 2006; 17(12): 5141 - 5152. [Abstract] [Full Text] [PDF]

				F. Zhang, Q. Wen, S. Mergler, H. Yang, Z. Wang, V. N. Bildin, and P. S. Reinach PKC Isoform-Specific Enhancement of Capacitative Calcium Entry in Human Corneal Epithelial Cells. Invest. Ophthalmol. Vis. Sci., September 1, 2006; 47(9): 3989 - 4000. [Abstract] [Full Text] [PDF]

				D. G. Cronshaw, A. Kouroumalis, R. Parry, A. Webb, Z. Brown, and S. G. Ward Evidence that phospholipase C-dependent, calcium-independent mechanisms are required for directional migration of T lymphocytes in response to the CCR4 ligands CCL17 and CCL22 J. Leukoc. Biol., June 1, 2006; 79(6): 1369 - 1380. [Abstract] [Full Text] [PDF]

				L. J. Green, P. Marder, C. Ray, C. A. Cook, S. Jaken, L. C. Musib, R. S. Herbst, M. Carducci, C. D. Britten, M. Basche, et al. Development and Validation of a Drug Activity Biomarker that Shows Target Inhibition in Cancer Patients Receiving Enzastaurin, a Novel Protein Kinase C-{beta} Inhibitor. Clin. Cancer Res., June 1, 2006; 12(11): 3408 - 3415. [Abstract] [Full Text] [PDF]

				M. Rosenberg and S. Ravid Protein Kinase C{gamma} Regulates Myosin IIB Phosphorylation, Cellular Localization, and Filament Assembly Mol. Biol. Cell, March 1, 2006; 17(3): 1364 - 1374. [Abstract] [Full Text] [PDF]

				J. B. Barry and V. Giguere Epidermal Growth Factor-Induced Signaling in Breast Cancer Cells Results in Selective Target Gene Activation by Orphan Nuclear Receptor Estrogen-Related Receptor {alpha} Cancer Res., July 15, 2005; 65(14): 6120 - 6129. [Abstract] [Full Text] [PDF]

				R. Ginnan and H. A. Singer PKC-{delta}-dependent pathways contribute to PDGF-stimulated ERK1/2 activation in vascular smooth muscle Am J Physiol Cell Physiol, June 1, 2005; 288(6): C1193 - C1201. [Abstract] [Full Text] [PDF]

				A. Hurbin, J.-L. Coll, L. Dubrez-Daloz, B. Mari, P. Auberger, C. Brambilla, and M.-C. Favrot Cooperation of Amphiregulin and Insulin-like Growth Factor-1 Inhibits Bax- and Bad-mediated Apoptosis via a Protein Kinase C-dependent Pathway in Non-small Cell Lung Cancer Cells J. Biol. Chem., May 20, 2005; 280(20): 19757 - 19767. [Abstract] [Full Text] [PDF]

				S. Hautaniemi, S. Kharait, A. Iwabu, A. Wells, and D. A. Lauffenburger Modeling of signal-response cascades using decision tree analysis Bioinformatics, May 1, 2005; 21(9): 2027 - 2035. [Abstract] [Full Text] [PDF]

				S. Amos, P. M. Martin, G. A. Polar, S. J. Parsons, and I. M. Hussaini Phorbol 12-Myristate 13-Acetate Induces Epidermal Growth Factor Receptor Transactivation via Protein Kinase C{delta}/c-Src Pathways in Glioblastoma Cells J. Biol. Chem., March 4, 2005; 280(9): 7729 - 7738. [Abstract] [Full Text] [PDF]

				S. Banerjee, K. Sengupta, N. K. Saxena, K. Dhar, and S. K. Banerjee Epidermal Growth Factor Induces WISP-2/CCN5 Expression in Estrogen Receptor-{alpha}-Positive Breast Tumor Cells through Multiple Molecular Cross-talks Mol. Cancer Res., March 1, 2005; 3(3): 151 - 162. [Abstract] [Full Text] [PDF]

				R. Sun, P. Gao, L. Chen, D. Ma, J. Wang, J. J. Oppenheim, and N. Zhang Protein Kinase C {zeta} Is Required for Epidermal Growth Factor-Induced Chemotaxis of Human Breast Cancer Cells Cancer Res., February 15, 2005; 65(4): 1433 - 1441. [Abstract] [Full Text] [PDF]

				M. D. Burdick, L. A. Murray, M. P. Keane, Y. Y. Xue, D. A. Zisman, J. A. Belperio, and R. M. Strieter CXCL11 Attenuates Bleomycin-induced Pulmonary Fibrosis via Inhibition of Vascular Remodeling Am. J. Respir. Crit. Care Med., February 1, 2005; 171(3): 261 - 268. [Abstract] [Full Text] [PDF]

				M. Bustamante, U. Hasler, O. Kotova, A. V. Chibalin, D. Mordasini, M. Rousselot, A. Vandewalle, P.-Y. Martin, and E. Feraille Insulin potentiates AVP-induced AQP2 expression in cultured renal collecting duct principal cells Am J Physiol Renal Physiol, February 1, 2005; 288(2): F334 - F344. [Abstract] [Full Text] [PDF]

				V. Laurent-Matha, S. Maruani-Herrmann, C. Prebois, M. Beaujouin, M. Glondu, A. Noel, M. L. Alvarez-Gonzalez, S. Blacher, P. Coopman, S. Baghdiguian, et al. Catalytically inactive human cathepsin D triggers fibroblast invasive growth J. Cell Biol., January 31, 2005; 168(3): 489 - 499. [Abstract] [Full Text] [PDF]

				M. M. Monick, K. Cameron, J. Staber, L. S. Powers, T. O. Yarovinsky, J. G. Koland, and G. W. Hunninghake Activation of the Epidermal Growth Factor Receptor by Respiratory Syncytial Virus Results in Increased Inflammation and Delayed Apoptosis J. Biol. Chem., January 21, 2005; 280(3): 2147 - 2158. [Abstract] [Full Text] [PDF]

				A. Llado, F. Tebar, M. Calvo, J. Moreto, A. Sorkin, and C. Enrich Protein KinaseC{delta}-Calmodulin Crosstalk Regulates Epidermal Growth Factor Receptor Exit from Early Endosomes Mol. Biol. Cell, November 1, 2004; 15(11): 4877 - 4891. [Abstract] [Full Text] [PDF]