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J. Biol. Chem., Vol. 281, Issue 15, 9977-9986, April 14, 2006

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Characterization of p87^PIKAP, a Novel Regulatory Subunit of Phosphoinositide 3-Kinase That Is Highly Expressed in Heart and Interacts with PDE3B^*

Philipp Voigt, Martin B. Dorner, and Michael Schaefer¹

From the Institut für Pharmakologie, Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin, Thielallee 67-73, 14195 Berlin, Germany and Molekulare Immunologie, Robert Koch-Institut, Nordufer 20, 13353 Berlin, Germany

Phosphoinositide 3-kinase (PI3K) has been implicated in a vast array of physiological settings including the activation of different leukocyte species and the regulation of myocardial contractility. Activation of PI3K is primarily mediated by G subunits of heterotrimeric G proteins, which are recognized by a p101 regulatory subunit. Here, we describe the identification and characterization of a novel regulatory subunit of PI3K, which we termed p87^PIKAP (PI3K adapter protein of 87 kDa). It is homologous to p101 in areas that we have recently shown that they mediate binding to the catalytic p110 subunit and to G. Like p101, p87^PIKAP binds to both p110 and G and mediates activation of p110 downstream of G protein-coupled receptors. In contrast to p101, p87^PIKAP is highly expressed in heart and may therefore be crucial to PI3K cardiac function. Moreover, p87^PIKAP and p101 are both expressed in dendritic cells, macrophages, and neutrophils, raising the possibility of regulatory subunit-dependent differences in PI3K signaling within the same cell type. We further provide evidence that p87^PIKAP physically interacts with phosphodiesterase (PDE) 3B, suggesting that p87^PIKAP is also involved in the recently described noncatalytic scaffolding interaction of p110 with PDE3B. However, coexpression of PDE3B and PI3K subunits was not sufficient to reconstitute the regulatory effect of PI3K on PDE3B activity observed in heart, implying further molecules to be present in the complex regulating PDE3B in heart.

Received for publication, November 22, 2005 , and in revised form, February 8, 2006.

^* This work was supported by the Deutsche Forschungsgemeinschaft. 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.

The nucleotide sequence(s) reported in this paper has been submitted to the DDBJ/GenBank^TM/EBI Data Bank with accession number(s) AY753194 [GenBank] and DQ295832 [GenBank] .

¹ To whom correspondence should be addressed. Tel.: 49-30-8445-1863; Fax: 49-30-8445-1818; E-mail: m.schaefer{at}charite.de.

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