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Molecular and Cellular Biology, September 1999, p. 6286-6296, Vol. 19, No. 9
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Insulin-Induced Phosphorylation and Activation of Cyclic Nucleotide Phosphodiesterase 3B by the Serine-Threonine Kinase Akt

Tadahiro Kitamura,1 Yukari Kitamura,1 Shoji Kuroda,1 Yasuhisa Hino,1 Miwa Ando,1 Ko Kotani,1 Hiroaki Konishi,2 Hidenori Matsuzaki,2 Ushio Kikkawa,2 Wataru Ogawa,1,* and Masato Kasuga1

Second Department of Internal Medicine, Kobe University School of Medicine, Chuo-ku, Kobe 650-0017,1 and Biosignal Research Center, Kobe University, Nada-ku, Kobe 657-8501,2 Japan

Received 4 February 1999/Returned for modification 22 March 1999/Accepted 23 June 1999

Cyclic nucleotide phosphodiesterase (PDE) is an important regulator of the cellular concentrations of the second messengers cyclic AMP (cAMP) and cGMP. Insulin activates the 3B isoform of PDE in adipocytes in a phosphoinositide 3-kinase-dependent manner; however, downstream effectors that mediate signaling to PDE3B remain unknown. Insulin-induced phosphorylation and activation of endogenous or recombinant PDE3B in 3T3-L1 adipocytes have now been shown to be inhibited by a dominant-negative mutant of the serine-threonine kinase Akt, suggesting that Akt is necessary for insulin-induced phosphorylation and activation of PDE3B. Serine-273 of mouse PDE3B is located within a motif (RXRXXS) that is preferentially phosphorylated by Akt. A mutant PDE3B in which serine-273 was replaced by alanine was not phosphorylated either in response to insulin in intact cells or by purified Akt in vitro. In contrast, PDE3B mutants in which alanine was substituted for either serine-296 or serine-421, each of which lies within a sequence (RRXS) preferentially phosphorylated by cAMP-dependent protein kinase, were phosphorylated by Akt in vitro or in response to insulin in intact cells. Moreover, the serine-273 mutant of PDE3B was not activated by insulin when expressed in adipocytes. These results suggest that PDE3B is a physiological substrate of Akt and that Akt-mediated phosphorylation of PDE3B on serine-273 is important for insulin-induced activation of PDE3B.

* Corresponding author. Mailing address: Second Department of Internal Medicine, Kobe University School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan. Phone: 81-78-382-5861. Fax: 81-78-382-2080. E-mail: ogawa{at}med.kobe-u.ac.jp.

Molecular and Cellular Biology, September 1999, p. 6286-6296, Vol. 19, No. 9
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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