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J. Biol. Chem., Vol. 280, Issue 45, 37610-37615, November 11, 2005

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A Protein Kinase C/Ras/ERK Signaling Pathway Activates Myeloid Fibronectin Receptors by Altering 1 Integrin Sialylation^*

Eric C. Seales12, Faheem M. Shaikh1, Alencia V. Woodard-Grice, Pooja Aggarwal, Alexis C. McBrayer, Kristin M. Hennessy, and Susan L. Bellis3

From the Departments of Pathology and Physiology and Biophysics, University of Alabama at Birmingham, Birmingham, Alabama 35294

Here we report that myeloid cells differentiating along the monocyte/macrophage lineage down-regulate the ST6Gal-I sialyltransferase via a protein kinase C/Ras/ERK signaling cascade. In consequence, the 1 integrin subunit becomes hyposialylated, which stimulates the ligand binding activity of 51 fibronectin receptors. Pharmacologic inhibitors of protein kinase C, Ras, and MEK, but not phosphoinositide 3-kinase, block ST6Gal-I down-regulation, integrin hyposialylation, and fibronectin binding. In contrast, constitutively active MEK stimulates these same events, indicating that ERK is both a necessary and sufficient activator of hyposialylation-dependent integrin activation. Consistent with the enhanced activity of hyposialylated cell surface integrins, purified 51 receptors bind fibronectin more strongly upon enzymatic desialylation, an effect completely reversed by resialylation of these integrins with recombinant ST6Gal-I. Finally, we have mapped the N-glycosylation sites on the 1 integrin to better understand the potential effects of differential sialylation on integrin structure/function. Notably, there are three N-glycosylated sites within the 1 I-like domain, a region that plays a crucial role in ligand binding. Our collective results suggest that variant sialylation, induced by a specific signaling cascade, mediates the sustained increase in cell adhesiveness associated with monocytic differentiation.

Received for publication, August 2, 2005 , and in revised form, September 9, 2005.

^* This project was supported in part by National Institutes of Health Grants R01 CA84248 and 5 P60 AR20614-23 as well as grants from the Mizutani Foundation for Glycoscience and the University of Alabama Cell Adhesion and Matrix Research Center. 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.

¹ These authors contributed equally to this work.

² Supported by a pre-doctoral fellowship from the "Training Program in Rheumatic Diseases Research" Training Grant 2 T32 AR07450.

³ To whom correspondence should be addressed: Dept. of Physiology and Biophysics, 982A MCLM, 1918 University Blvd., Birmingham, AL 35294. Tel.: 205-934-3441; Fax: 205-975-9028; E-mail: bellis{at}physiology.uab.edu.

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