MAP1

MAP1 (PF3D7_0811600) is a Plasmodium falciparum mitogen-activated protein kinase homologue defined by a conserved MAPK catalytic domain and a distinctive highly charged C-terminal extension carrying two sets of repeated amino acid motifs (PMID:8921836). Genetic ablation studies establish that MAP1 is dispensable for asexual blood-stage schizogony, gametocytogenesis, gametogenesis, and sporogony, both as a single knockout and in combination with PfMAP-2 (PMID:17651389, PMID:32681115). The elevation of PfMAP-2 protein levels in MAP1-null parasites points to a functional relationship between the two kinases in which loss of MAP1 is buffered by compensatory adaptation (PMID:17651389). Upstream regulation distinguishes MAP1 from PfMAP-2: the NIMA-family kinase Pfnek3 phosphorylates and activates PfMAP-2 but neither phosphorylates nor stimulates MAP1, indicating MAP1 is not a Pfnek3 substrate (PMID:17064692). Beyond these findings, the direct catalytic substrates, activating kinase, and precise cellular role of MAP1 have not been characterized in the available corpus.

1. 1996 Medium

   Establishing whether P. falciparum encodes a MAP kinase and what distinguishes it structurally was the first question; identifying MAP1 as a MAPK homologue with a conserved catalytic domain and a unique charged C-terminal repeat extension defined the protein as a candidate signalling kinase.

   Evidence Degenerate-oligonucleotide PCR, sequence comparison, Northern blot, and chromosome mapping

   PMID:8921836

   Open questions at the time

   • No catalytic activity or substrate demonstrated
   • Function of the C-terminal charged repeat extension unknown
   • Protein-level expression and localization not established
2. 2000 Low

   Whether the MAP1 orthologue is expressed outside blood stages was addressed by showing pymap-1 transcript in both liver and erythrocytic stages of P. yoelii, extending the potential activity window across the life cycle.

   Evidence RT-PCR and Northern blot of liver- and blood-stage RNA from infected mice (P. yoelii ortholog)

   PMID:11087914

   Open questions at the time

   • Transcript-level detection only, no protein or functional consequence shown
   • Result is from P. yoelii, not P. falciparum
   • Does not indicate what MAP1 does in liver stages
3. 2006 Medium

   The question of MAP1's upstream activator was tested against the NIMA-kinase Pfnek3; the finding that Pfnek3 activates PfMAP-2 but not MAP1 established that Pfnek3-mediated activation is specific to PfMAP-2 and that MAP1's activating kinase remains unidentified.

   Evidence In vitro kinase assay with recombinant proteins

   PMID:17064692

   Open questions at the time

   • The true upstream activating kinase of MAP1 is not identified
   • In vitro negative result; a cellular activator interaction is not excluded
   • No downstream substrate of MAP1 tested
4. 2007 High

   Whether MAP1 is essential was answered by knockout, showing dispensability across asexual and sexual stages and sporogony while PfMAP-2 protein levels rose, establishing MAP1 as non-essential under standard conditions but functionally intertwined with PfMAP-2.

   Evidence Reverse-genetics knockout with multi-stage phenotyping and Western blot for PfMAP-2 levels

   PMID:17651389

   Open questions at the time

   • Molecular basis of PfMAP-2 elevation (compensation) not defined
   • The specific process MAP1 normally performs remains unknown
   • No conditional or stress-condition phenotype examined
5. 2020 High

   Whether combined loss of MAP1 and PfMAP-2 unmasks a phenotype was tested with single and double null mutants, confirming dispensability for asexual proliferation, sexual commitment, and gametocytogenesis and reinforcing that neither kinase is required for these stages.

   Evidence Single and double null mutant genetics with phenotypic analysis of asexual and sexual blood stages

   PMID:32681115

   Open questions at the time

   • No positive functional role for MAP1 identified even in the double-null context
   • Substrates and signalling output still undefined
   • Whether a phenotype exists in transmission or liver stages not fully resolved

• The catalytic substrates, physiological activating kinase, and the specific cellular process performed by MAP1 remain unidentified, as does the mechanistic basis of its functional relationship with PfMAP-2.
• No direct MAP1 substrate identified
• Upstream activating kinase unknown
• Mechanism of PfMAP-2 compensation upon MAP1 loss uncharacterized