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J. Biol. Chem., Vol. 282, Issue 8, 5653-5660, February 23, 2007

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Association of CD38 with Nonmuscle Myosin Heavy Chain IIA and Lck Is Essential for the Internalization and Activation of CD38^*

So-Young Rah¹, Kwang-Hyun Park, Tae-Sik Nam, Sang-Jin Kim, Hyuntae Kim, Mie-Jae Im, and Uh-Hyun Kim²

From the Department of Biochemistry and the Institute of Cardiovascular Research, Chonbuk National University Medical School, Jeonju 561-182, Republic of Korea

Activation of CD38 in lymphokine-activated killer (LAK) cells involves interleukin-8 (IL8)-mediated protein kinase G (PKG) activation and results in an increase in the sustained intracellular Ca²⁺ concentration ([Ca²⁺]_i), cADP-ribose, and LAK cell migration. However, direct phosphorylation or activation of CD38 by PKG has not been observed in vitro. In this study, we examined the molecular mechanism of PKG-mediated activation of CD38. Nonmuscle myosin heavy chain IIA (MHCIIA) was identified as a CD38-associated protein upon IL8 stimulation. The IL8-induced association of MHCIIA with CD38 was dependent on PKG-mediated phosphorylation of MHCIIA. Supporting these observations, IL8- or cell-permeable cGMP analog-induced formation of cADP-ribose, increase in [Ca²⁺]_i, and migration of LAK cells were inhibited by treatment with the MHCIIA inhibitor blebbistatin. Binding studies using purified proteins revealed that the association of MHCIIA with CD38 occurred through Lck, a tyrosine kinase. Moreover, these three molecules co-immunoprecipitated upon IL8 stimulation of LAK cells. IL8 treatment of LAK cells resulted in internalization of CD38, which co-localized with MHCIIA and Lck, and blebbistatin blocked internalization of CD38. These findings demonstrate that the association of phospho-MHCIIA with Lck and CD38 is a critical step in the internalization and activation of CD38.

Received for publication, October 6, 2006 , and in revised form, November 14, 2006.

^* This work was supported by Korea Research Foundation Grant KRF-2004-005-E00108 (to U.-H. Kim). 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 Recipient of a BK21 fellowship from the Korea Ministry of Education.

² To whom correspondence should be addressed: Dept. of Biochemistry, Chonbuk National University Medical School, Keumam-dong, Jeonju 561-182, Republic of Korea. Tel.: 82-63-270-3083; Fax: 82-63-274-9833; E-mail: uhkim{at}chonbuk.ac.kr.

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