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J. Biol. Chem., Vol. 283, Issue 33, 22513-22528, August 15, 2008

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CD44-Epidermal Growth Factor Receptor Interaction Mediates Hyaluronic Acid-promoted Cell Motility by Activating Protein Kinase C Signaling Involving Akt, Rac1, Phox, Reactive Oxygen Species, Focal Adhesion Kinase, and MMP-2^*

Youngmi Kim, Yun-Sil Lee, Jongseon Choe^¶, Hansoo Lee, Young-Myeong Kim^¶, and Dooil Jeoung¹

From the School of Biological Sciences, College of Natural Sciences, Kangwon National University, Chunchon 200-701, Laboratory of Radiation Effect, Division of Radiation Biology, Korea Institute of Radiological and Medical Sciences, Seoul 139-706, and the ^¶School of Medicine, Kangwon National University, Chunchon 200-701, Korea

Hyaluronic acid (HA) is known to play an important role in motility of tumor cells. However, the molecular mechanisms associated with HA-promoted melanoma cell motility are not fully understood. Treatment of cells with HA was shown to increase the production of reactive oxygen species (ROS) in a CD44-dependent manner. Antioxidants, such as N-acetyl-L-cysteine and seleno-L-methionine, prevented HA from enhancing cell motility. Protein kinase C (PKC)- and PKC were responsible for increased Rac1 activity, production of ROS, and mediated HA-promoted cell motility. HA increased Rac1 activity via CD44, PKC, and PKC. Transfection with dominant negative and constitutive active Rac1 mutants demonstrated that Rac1 was responsible for the increased production of ROS and cell motility by HA. Inhibition of NADPH oxidase by diphenylene iodonium and down-regulation of p47^Phox and p67^Phox decreased the ROS level, suggesting that NADPH oxidase is the main source of ROS production. Rac1 increased phosphorylation of FAK. FAK functions downstream of and is necessary for HA-promoted cell motility. Secretion and expression of MMP-2 were increased by treatment with HA via the action of PKC, PKC, and Rac1 and the production of ROS and FAK. Ilomastat, an inhibitor of MMP-2, exerted a negative effect on HA-promoted cell motility. HA increased interaction between CD44 and epidermal growth factor receptor (EGFR). AG1478, an inhibitor of EGFR, decreased phosphorylation of PKC, PKC, and Rac1 activity and suppressed induction of p47^Phox and p67^Phox. These results suggest that CD44-EGFR interaction is necessary for HA-promoted cell motility by regulating PKC signaling. EGFR-Akt interaction promoted by HA was responsible for the increased production of ROS and HA-promoted cell motility. In summary, HA promotes CD44-EGFR interaction, which in turn activates PKC signaling, involving Akt, Rac1, Phox, and the production of ROS, FAK, and MMP-2, to enhance melanoma cell motility.

Received for publication, October 5, 2007 , and in revised form, June 18, 2008.

^* This work was supported by grants from the Korea Research Foundation and Vascular Research Center, by Grant A050260 from the Ministry of Health and Welfare of Korea, and by Grant FG06-2-23 from the 21st Century Frontier Functional Human Genome Project from the Ministry of Science & Technology in Korea. 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 To whom correspondence should be addressed: Tel.: 82-33-250-8518; Fax: 82-33-242-0459; E-mail: jeoungd{at}kangwon.ac.kr.

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