Pfnek3: An atypical activator of a MAP kinase in Plasmodium falciparum

Abstract

The canonical mitogen-activated protein kinase (MAPK) signal cascade was previously suggested to be atypical in the malaria parasite. This raises queries on the existence of alternative mediators of plasmodial MAPK pathways. This study describes, Pfnek3, a malarial protein kinase belonging to the NIMA (Never in Mitosis, Aspergillus) family. Endogenous Pfnek3 is expressed during late asexual to gametocyte stages and lacks some classical protein kinase sequence motifs. Moreover, Pfnek3 is phylogenetically distant from mammalian NIMA-kinases. Recombinant Pfnek3 was able to phosphorylate and stimulate a malarial MAPK (Pfmap2). Contrastingly, this was not observed with two other kinases, Pfmap1 and human MAPK1, suggesting that the Pfnek3-Pfmap2 interaction may be specific for Pfmap2 regulation. In summary, our data reveal a malarial NIMA-kinase with the potential to regulate a MAPK. Possessing biochemical properties divergent from classical mammalian NIMA-kinases, Pfnek3 could potentially be an attractive target for parasite-selective anti-malarials.

The kinomes of apicomplexan parasites

“…Pfnek-2 is essential for transmission to the mosquito, and studies with the P. berghei orthologues identified a defect in meiosis in parasites lacking the enzyme, as was the case for Pbnek-4 [86,87]. Pfnek-3 has been reported to activate Pfmap-2 in vitro, like Pfnek-1 [88]. A succinct phylogenetic tree of Plasmodium NEKs in relation to other members of the family has been published [86], and a more thorough analysis is in preparation (Luc Reininger, personal communication).…”

An evolutionary perspective on the kinome of malaria parasites

“…The expansion of the NEK family is seen to a lesser extent in Trichomonas vaginalis [83] and trypanosomes [93], which are also parasitic excavates with elaborate flagellar systems. Three of the four Plasmodium NEK family members are expressed predominantly in sexual stages [48,49,94], which include the only flagellated cell form in the Plasmodium life cycle, the male gamete; however, only one Pfnek has been clearly shown to be male-specific [95,96], whereas two others are associated with female development and appear to be involved in meiosis [48,49].…”

Molecular cloning and characterization of mitogen-activated protein kinase 2 inTrypanosoma cruzi

“…In malaria parasites, P. berghei and P. falciparum, MAP kinase-2 is required for male gamete formation. [9][10][11] An atypical activator of MAPK was reported in P. falciparum [12][13][14] and the typical three-component cascade signaling does not exist in malaria parasites, suggesting that mechanisms for the activation of MAP kinase in malaria are different than their mammalian host. Giardia lamblia, an intestinal protozoan parasite, possesses homologues of ERK1 and ERK2, which are involved in encystations.…”