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Alkaline ceramidase 2 regulates β1 integrin maturation and cell adhesion

Wei Sun^*,1, Wei Hu^,1, Ruijuan Xu^*,1, Junfei Jin, Zdzislaw M. Szulc, Guofeng Zhang, Sehamuddin H. Galadari, Lina M. Obeid^*,,|| and Cungui Mao^*,,2

^* Department of Medicine and

Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, South Carolina, USA;

Division of Bioengineering and Physical Sciences, National Institutes of Health, Bethesda, Maryland, USA;

Department of Biochemistry, Faculty of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates; and

^|| Ralph H. Johnson Veterans Administration Hospital, Charleston, South Carolina, USA

² Correspondence: Division of General Internal Medicine, 114 Doughty St., Rm. 605 STB, PO Box 250779, Charleston, SC 29425, USA. E-mail: maoc{at}musc.edu

The polypeptide core of the integrin β1 subunit (β1) is glycosylated sequentially in the endoplasmic reticulum and the Golgi complex to form β1 precursor and mature β1, respectively. The β1 precursor to mature β1 conversion, termed β1 maturation, regulates the cell surface levels and function of β1-containing integrins, β1 integrins. Here we demonstrate that the human alkaline ceramidase 2 (ACER2), a Golgi enzyme, regulates β1 maturation by controlling the generation of sphingosine. ACER2 overexpression inhibited β1 maturation, thus leading to a decrease in the levels of mature β1 in T-REx HeLa cells, whereas RNA interference-mediated knockdown of ACER2 enhanced β1 maturation in MCF-7 cells. ACER2 overexpression decreased the cell surface levels of β1 integrins, thus inhibiting cell adhesion to fibronectin or collagen, whereas ACER2 knockdown has the opposite effects. Treatment with all-trans retinoic acid (ATRA) increased both the expression of ACER2 and the generation of sphingosine in HeLa cells and inhibited β1 maturation. ACER2 knockdown attenuated the inhibitory effects of ATRA on both β1 maturation and cell adhesion. In contrast, treatment with phorbol myristate acetate (PMA), a protein kinase C activator, decreased the expression of ACER2 and sphingosine in T-REx HeLa cells, thus enhancing β1 maturation. ACER2 overexpression inhibited the stimulatory effects of PMA on both β1 maturation and cell adhesion. These results suggest that the ACER2/sphingosine pathway plays an important role in regulating β1 maturation and cell adhesion mediated by β1 integrins.—Sun, W., Hu, W., Xu, R., Jin, J., Szulc, Z. M., Zhang, G., Galadari, S. H., Obeid, L. M, Mao, C. Alkaline ceramidase 2 regulates β1 integrin maturation and cell adhesion.

Key Words: retinoic acid • protein kinase C • Golgi • sphingolipid

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				R. Xu, W. Sun, J. Jin, L. M. Obeid, and C. Mao Role of alkaline ceramidases in the generation of sphingosine and its phosphate in erythrocytes FASEB J, July 1, 2010; 24(7): 2507 - 2515. [Abstract] [Full Text] [PDF]

				W. Sun, J. Jin, R. Xu, W. Hu, Z. M. Szulc, J. Bielawski, L. M. Obeid, and C. Mao Substrate Specificity, Membrane Topology, and Activity Regulation of Human Alkaline Ceramidase 2 (ACER2) J. Biol. Chem., March 19, 2010; 285(12): 8995 - 9007. [Abstract] [Full Text] [PDF]