Atypical MAP kinases - new insights and directions from amoeba.

Mitogen-activated protein kinases (MAPKs) have been the focus of many studies over the past several decades, but the understanding of one subgroup of MAPKs, orthologs of MAPK15, known as atypical MAPKs, has lagged behind others. In most organisms, specific activating signals or downstream responses of atypical MAPK signaling pathways have not yet been identified even though these MAPKs are associated with many eukaryotic processes, including cancer and embryonic development. In this Review, we discuss recent studies that are shedding new light on both the regulation and function of atypical MAPKs in different organisms.

An atypical MAPK regulates translocation of a GATA transcription factor in response to chemoattractant stimulation.

The Dictyostelium atypical mitogen-activated protein kinase (MAPK) Erk2 is required for chemotactic responses to cAMP as amoeba undergo multicellular development. In this study, Erk2 was found to be essential for the cAMP-stimulated translocation of the GATA transcription factor GtaC as indicated by the distribution of a GFP-GtaC reporter. Erk2 was also found to be essential for the translocation of GtaC in response to external folate, a foraging signal that directs the chemotaxis of amoeba to bacteria.

MAPK docking motif in the Dictyostelium Gα2 subunit is required for aggregation and transcription factor translocation.

Some G protein alpha subunits contain a mitogen-activated protein kinase (MAPK) docking motif (D-motif) near the amino terminus that can impact cellular responses to external signals. The Dictyostelium Gα2 G protein subunit is required for chemotaxis to cAMP during the onset of multicellular development and this subunit contains a putative D-motif near the amino terminus. The Gα2 subunit D-motif was altered to examine its potential role in chemotaxis and multicellular development.

Mitogen-activated protein kinase regulation of the phosphodiesterase RegA in early development.

Mitogen-activated protein kinase (MAPK) regulation of cAMP-specific phosphodiesterase function has been demonstrated in mammalian cells and suspected to occur in other eukaryotes. Epistasis analysis in the soil amoeba suggests the atypical MAPK Erk2 downregulates the function of the cAMP-specific phosphodiesterase RegA to regulate progression of the developmental life cycle. A putative MAPK docking motif located near a predicted MAPK phosphorylation site was characterized for contributions to RegA function and binding to Erk2 because a similar docking motif has been previously characterized in the mammalian PDE4D phosphodiesterase.

Multiple phosphorylation sites on the RegA phosphodiesterase regulate Dictyostelium development.

In Dictyostelium, the intracellular cAMP-specific phosphodiesterase RegA is a negative regulator of cAMP-dependent protein kinase (PKA), a key determinant in the timing of developmental morphogenesis and spore formation. To assess the role of protein kinases in the regulation of RegA function, this study identified phosphorylation sites on RegA and characterized the role of these modifications through the analysis of phospho-mimetic and phospho-ablative mutations. Mutations affecting residue T676 of RegA, a presumed target of the atypical MAP kinase Erk2, altered the rate of development and impacted cell distribution in chimeric organisms suggesting that phosphorylation of this residue reduces RegA function and regulates cell localization during multicellular development.