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J. Biol. Chem., Vol. 283, Issue 9, 5589-5597, February 29, 2008

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Role of Ca²⁺/Calmodulin-PfPKB Signaling Pathway in Erythrocyte Invasion by Plasmodium falciparum^*

From the Eukaryotic Gene Expression Laboratory, National Institute of Immunology, New Delhi-110067, India

Molecular mechanisms by which signaling pathways operate in the malaria parasite and control its development are promiscuous. Recently, we reported the identification of a signaling pathway in Plasmodium falciparum, which involves activation of protein kinase B-like enzyme (PfPKB) by calcium/calmodulin (Vaid, A., and Sharma, P. (2006) J. Biol. Chem. 281, 27126–27133). Studies carried out to elucidate the function of this pathway suggested that it may be important for erythrocyte invasion. Blocking the function of the upstream activators of this pathway, calmodulin and phospholipase C, resulted in impaired invasion. To evaluate if this signaling cascade controls invasion by regulating PfPKB, inhibitors against this kinase were developed. PfPKB inhibitors dramatically reduced the ability of the parasite to invade erythrocytes. Furthermore, we demonstrate that PfPKB associates with actin-myosin motor and phosphorylates PfGAP45 (glideosome-associated protein 45), one of the important components of the motor complex, which may help explain its role in erythrocyte invasion.

Received for publication, October 11, 2007 , and in revised form, December 17, 2007.

^* This work was supported in part by The Wellcome Trust Senior Research Fellowship (to P. S.). 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 on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. I–V.

¹ Recipient of Junior Research fellowship from the Center for Scientific and Industrial Research, India.

² To whom correspondence should be addressed. Tel.: 91-11-26703791; Fax: 91-11-26742125; E-mail: pushkar{at}nii.res.in.

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