spacer gif spacer gif spacer gif spacer gif spacer gif
QUICK SEARCH:   [advanced]


spacer gif
     Home     Help     Feedback     Subscriptions     Archive     Search     Table of Contents    

First published online 30 July 2003
doi: 10.1242/jcs.00693

This Article
Right arrow Figures Only
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
jcs.00693v1
116/18/3749    most recent
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Koivisto, L.
Right arrow Articles by Larjava, H.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Koivisto, L.
Right arrow Articles by Larjava, H.
Journal of Cell Science 116, 3749-3760 (2003)
doi: 10.1242/jcs.00693

Research Article

Glycogen synthase kinase-3 regulates formation of long lamellipodia in human keratinocytes

Leeni Koivisto1, Keyhan Alavian1, Lari Häkkinen1, Steven Pelech2, Christopher A. McCulloch3 and Hannu Larjava1,*

1 University of British Columbia, Faculty of Dentistry, Department of Oral Biological and Medical Sciences, 2199 Wesbrook Mall, Vancouver, BC V6T 1Z3, Canada
2 Kinexus Bioinformatics Corporation, Suite 401, 2389 Health Sciences Mall, Vancouver, BC V6T 1Z4, Canada
3 University of Toronto, Faculty of Dentistry, Department of Biological and Diagnostic Sciences, 150 College Street, Toronto, ON M5S 3E2, Canada

* Author for correspondence (e-mail: larjava{at}interchange.ubc.ca)

Accepted 28 May 2003

During wound healing, keratinocytes initiate migration from the wound edge by extending lamellipodia into a fibronectin-rich provisional matrix. While lamellipodia-like structures are also found in cultured keratinocytes exposed to epidermal growth factor (EGF), the signaling pathway that regulates the formation of these structures is not defined. In cultured human keratinocytes seeded on fibronectin, we found that protein-serine/threonine kinase inhibitors including staurosporine, induced concentration-dependent formation of extended lamellipodia (E-lams). The formation of E-lams was inhibited by the proteintyrosine kinase inhibitors herbimycin A and genistein and augmented by the protein-tyrosine phosphatase inhibitor sodium orthovanadate. Staurosporine treatment induced relocation of tyrosine phosphorylated phospholipase C-{gamma}1 (PLC-{gamma}1) to the tips of lamellipodia where actin assembly was initiated. Consistent with an involvement of PLC-{gamma}1 in E-lam formation, intracellular free calcium (Ca2+) was elevated during the formation of E-lams and conversely, E-lam formation was blocked by intracellular Ca2+ chelation with BAPTA/AM, but not by extracellular reduction of Ca2+ by EGTA. Notably, glycogen synthase kinase-3{alpha}/ß (GSK-3{alpha}/ß) was activated by staurosporine as evidenced by reduced phosphorylation on Ser-21/9. Suppression of GSK-3 activity by LiCl2 or by a specific chemical inhibitor, SB-415286, blocked E-lam formation but without altering cell spreading. Furthermore, GSK-3 inhibitors blocked both staurosporine- and EGF-induced keratinocyte migration in scratch-wounded cultures. We propose that GSK-3 plays a crucial role in the formation of long lamellipodia in human keratinocytes and is potentially a central regulatory molecule in epithelial cell migration during wound healing.

Key words: Fibronectin, Wound healing, Calcium, EGF, Migration




This article has been cited by other articles:


Home page
 GENES CELLSHome page
H. Yamamoto, S. K. Yoo, M. Nishita, A. Kikuchi, and Y. Minami
Wnt5a modulates glycogen synthase kinase 3 to induce phosphorylation of receptor tyrosine kinase Ror2.
Genes Cells, November 1, 2007; 12(11): 1215 - 1223.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
S. Basu, N. T. Ray, S. J. Atkinson, and H. E. Broxmeyer
Protein Phosphatase 2A Plays an Important Role in Stromal Cell-Derived Factor-1/CXC Chemokine Ligand 12-Mediated Migration and Adhesion of CD34+ Cells
J. Immunol., September 1, 2007; 179(5): 3075 - 3085.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Cell. Biol.Home page
X. Cai, M. Li, J. Vrana, and M. D. Schaller
Glycogen synthase kinase 3- and extracellular signal-regulated kinase-dependent phosphorylation of paxillin regulates cytoskeletal rearrangement.
Mol. Cell. Biol., April 1, 2006; 26(7): 2857 - 2868.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Cell. Biol.Home page
T. Kobayashi, S.-i. Hino, N. Oue, T. Asahara, M. Zollo, W. Yasui, and A. Kikuchi
Glycogen Synthase Kinase 3 and h-prune Regulate Cell Migration by Modulating Focal Adhesions
Mol. Cell. Biol., February 1, 2006; 26(3): 898 - 911.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
Y.-I. Lee, M. Seo, Y. Kim, S.-Y. Kim, U. G. Kang, Y.-S. Kim, and Y.-S. Juhnn
Membrane Depolarization Induces the Undulating Phosphorylation/Dephosphorylation of Glycogen Synthase Kinase 3{beta}, and This Dephosphorylation Involves Protein Phosphatases 2A and 2B in SH-SY5Y Human Neuroblastoma Cells
J. Biol. Chem., June 10, 2005; 280(23): 22044 - 22052.
[Abstract] [Full Text] [PDF]

Home page
 J. Cell Sci.Home page
G. Bazzoni, P. Tonetti, L. Manzi, M. R. Cera, G. Balconi, and E. Dejana
Expression of junctional adhesion molecule-A prevents spontaneous and random motility
J. Cell Sci., February 1, 2005; 118(3): 623 - 632.
[Abstract] [Full Text] [PDF]


© The Company of Biologists Ltd 2003