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J. Biol. Chem., Vol. 282, Issue 23, 17200-17209, June 8, 2007

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Protein Kinase A-regulated Nucleocytoplasmic Shuttling of Id1 during Angiogenesis^*

Koichi Nishiyama^¶1, Kentaro Takaji^||, Yasunobu Uchijima, Yukiko Kurihara, Tomoichiro Asano^**, Michihiro Yoshimura^¶, Hisao Ogawa^¶, and Hiroki Kurihara

From the Department of Physiological Chemistry and Metabolism and Department of Developmental Medical Technology (Sankyo), Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan, the ^¶Department of Cardiovascular Medicine and ^||Department of Cardiovascular Surgery, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto 860-8556, Japan, the Department of Internal Medicine, The Jikei University School of Medicine, 3-25-8 Nishi-shinbasi, Minato-ku, Tokyo 105-8461, Japan, and the ^**Department of Biomedical Chemistry, Hiroshima University Graduate School of Biomedical Sciences, Kasumi 1-2-3, Hiroshima 734-8551, Japan

Id1, an inhibitory partner of basic-helix-loop-helix transcriptional factors, has recently been recognized as a potent contributor to angiogenesis. However, the molecular mechanism underlying its role in angiogenesis remains essentially unknown. Herein we demonstrate the subcellular localization of Id1 to be altered depending on the cellular context of vascular endothelial cells. Id1 was localized in the nuclei of human umbilical vein endothelial cells (HUVECs) cultured on uncoated plates, whereas it was translocated to the cytoplasm in HUVECs on Matrigel along with the formation of capillary-like structures. Treatment with the nuclear export inhibitor leptomycin B and mutagenesis analysis using green fluorescent protein-fused Id1 revealed CRM1/exportin-dependent nuclear export of Id1 in HUVECs on Matrigel. This nuclear export of Id1 was inhibited by protein kinase A (PKA) activation by dibutyryl cyclic AMP and forskolin but was promoted by PKA inactivation by H-89 and MDL-12,330A. Mutagenesis analysis of Id1 showed the phosphorylation of Ser-5 to possibly mediate the effect of PKA. These results suggest the function of Id1 as a transcriptional factor to be controlled by nucleocytoplasmic shuttling during angiogenesis and that PKA might be involved in this process. This may serve as a novel mechanism regulating angiogenesis and as a possible target for therapeutic vascular regeneration.

Received for publication, December 19, 2006 , and in revised form, March 1, 2007.

^* 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: Dept. of Physiological Chemistry and Metabolism, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan. Tel.: 81-3-5841-3496; Fax: 81-3-5684-4958; E-mail: nkanako{at}bio.m.u-tokyo.ac.jp.

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