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J. Biol. Chem., Vol. 280, Issue 34, 30055-30062, August 26, 2005

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Protein Kinase A-dependent Phosphorylation of Lutheran/Basal Cell Adhesion Molecule Glycoprotein Regulates Cell Adhesion to Laminin 5^*

Emilie Gauthier¶, Cécile Rahuel¶, Marie Paule Wautier¶, Wassim El Nemer¶, Pierre Gane¶, Jean Luc Wautier¶, Jean Pierre Cartron¶, Yves Colin¶, and Caroline Le Van Kim¶||

From the INSERM U665, Paris, F-75015, Institut National de la Transfusion Sanguine, Paris, F-75015, France, and ^¶University Paris 7, Paris, F-75006, France

Lutheran (Lu) blood group and basal cell adhesion molecule (B-CAM) antigens reside on two glycoprotein (gp) isoforms Lu and Lu(v13) that belong to the Ig superfamily and differ only by the size of their cytoplasmic tail. Lu/B-CAM gps have been recognized as laminin 5 receptors on red blood cells and epithelial cells in multiple tissues. It has been shown that sickle red cells exhibit enhanced adhesion to laminin 5 when intracellular cAMP is up-regulated by physiological stimuli such as epinephrine and that this signaling pathway is protein kinase A- and Lu/B-CAM-dependent. In this study, we analyzed the relationship between the phosphorylation status of Lu/B-CAM gps and their adhesion function to laminin 5. We showed that Lu isoform was phosphorylated in sickle red cells as well as in erythroleukemic K562 and epithelial Madin-Darby canine kidney cells and that this phosphorylation is enhanced by different stimuli of the PKA pathway. Lu gp is phosphorylated by glycogen synthase kinase 3 , casein kinase II, and PKA at serines 596, 598, and 621, respectively. Alanine substitutions of serines 596 and 598 abolished phosphorylation by glycogen synthase kinase 3 and casein kinase II, respectively, but had no effect on adhesion of K562 cells to laminin under flow conditions. Conversely, mutation of serine 621 prevented phosphorylation by PKA and dramatically reduced cell adhesion. Furthermore, stimulation of K562 cells by epinephrine increased Lu gp phosphorylation by PKA and enhanced adhesion to laminin. It is postulated that modulation of the phosphorylation state of Lu gp might be a critical factor for the sickle red cells adhesiveness to laminin 5 in sickle cell disease.

Received for publication, March 25, 2005 , and in revised form, June 10, 2005.

^* This work was supported by the Institut National de la Transfusion Sanguine (INTS) and INSERM. 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: Caroline Le Van Kim, Inserm U665, INTS, 6 rue Alexandre Cabanel, 75015 Paris, France. Tel.: 33-1-44-49-30-46; Fax: 33-1-43-06-50-19; E-mail: levankim{at}idf.inserm.fr.

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