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Vol. 14, Issue 5, 2088-2103, May 2003

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Opposing Roles of Integrin 6A1 and Dystroglycan in Laminin-mediated Extracellular Signal-regulated Kinase Activation

Maria Ferletta ^* , Yamato Kikkawa ^* , Hao Yu , Jan F. Talts , Madeleine Durbeej , Arnoud Sonnenberg , Rupert Timpl ^||, Kevin P. Campbell , Peter Ekblom ^*  ¶ #, and Elke Genersch ^*  ¶

Department of Cell and Molecular Biology, Lund University, SE-22184 Lund, Sweden; ^* Department of Cell and Molecular Biology, Uppsala University, SE-75123 Uppsala, Sweden; Department of Physiology, Biophysics, and Neurology, Howard Hughes Medical Institute, University of Iowa, Iowa City, Iowa; The Netherlands Cancer Institute, Amsterdam, The Netherlands; and ^|| Max-Planck-Institute for Biochemistry, Martinsried, Germany

Submitted January 2, 2003; Accepted January 30, 2003
Monitoring Editor: Richard Hynes

Laminin–integrin interactions can in some settings activate the extracellular signal-regulated kinases (ERKs) but the control mechanisms are poorly understood. Herein, we studied ERK activation in response to two laminins isoforms (-1 and -10/11) in two epithelial cell lines. Both cell lines expressed 1-containing integrins and dystroglycan but lacked integrin 64. Antibody perturbation assays showed that both cell lines bound to laminin-10/11 via the 31and 61 integrins. Although laminin-10/11 was a stronger adhesion complex than laminin-1 for both cell lines, both laminins activated ERK in only one of the two cell lines. The ERK activation was mediated by integrin 61 and not by 31 or dystroglycan. Instead, we found that dystroglycan-binding domains of both laminin-1 and -10/11 suppressed integrin 61-mediated ERK activation. Moreover, the responding cell line expressed the two integrin 6 splice variants, 6A and 6B, whereas the nonresponding cell line expressed only 6B. Furthermore, ERK activation was seen in cells transfected with the integrin 6A subunit, but not in 6B-transfected cells. We conclude that laminin-1 and -10/11 share the ability to induce ERK activation, that this is regulated by integrin 6A1, and suggest a novel role for dystroglycan-binding laminin domains as suppressors of this activation.

Abbreviations used: ERK, extracellular signal-regulated kinase; MEK, mitogen-activated protein kinase kinase; LG, laminin globular module.

^¶ These authors contributed equally to this study.

^# Corresponding author. E-mail address: peter.ekblom{at}medkem.lu.se.

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