Abstract
Phosphoinositide-3-kinase enhancer (PIKE) proteins encoded by the PIKE/CENTG1 gene are members of the gamma subgroup of the Centaurin superfamily of small GTPases. They are characterized by their chimeric protein domain architecture consisting of a pleckstrin homology (PH) domain, a GTPase-activating (GAP) domain, Ankyrin repeats as well as an intrinsic GTPase domain. In mammals, three PIKE isoforms with variations in protein structure and subcellular localization are encoded by the PIKE locus. PIKE inactivation in mice results in a broad range of defects, including neuronal cell death during brain development and misregulation of mammary gland development. PIKE -/- mutant mice are smaller, contain less white adipose tissue, and show insulin resistance due to misregulation of AMP-activated protein kinase (AMPK) and insulin receptor/Akt signaling. here, we have studied the role of PIKE proteins in metabolic regulation in the fly. We show that the Drosophila PIKE homolog, ceng1A, encodes functional GTPases whose internal GAP domains catalyze their GTPase activity. To elucidate the biological function of ceng1A in flies, we introduced a deletion in the ceng1A gene by homologous recombination that removes all predicted functional PIKE domains. We found that homozygous ceng1A mutant animals survive to adulthood. In contrast to PIKE -/- mouse mutants, genetic ablation of Drosophila ceng1A does not result in growth defects or weight reduction. Although metabolic pathways such as insulin signaling, sensitivity towards starvation and mobilization of lipids under high fed conditions are not perturbed in ceng1A mutants, homozygous ceng1A mutants show a prolonged development in second instar larval stage, leading to a late onset of pupariation. In line with these results we found that expression of ecdysone inducible genes is reduced in ceng1A mutants. Together, we propose a novel role for Drosophila Ceng1A in regulating ecdysone signaling-dependent second to third instar larval transition.
Highlights
Centaurins comprise a family of multidomain proteins that regulate a variety of cellular processes including cell survival, cell cycle progression, cell migration, receptor and endosome trafficking, gene transcription as well as development of dendrites and synapse conductivity [1,2,3,4]
Similar to murine CENG1/Phosphoinositide-3-kinase enhancer (PIKE), it is predicted that the single Drosophila CENTG1 homolog centaurin gamma 1A (ceng1A) codes for three transcripts
In a step we checked if Ceng1A affects metabolic control on protein levels: Two of the major sensors for the nutritional status are AMPK and Akt: We found that AMPK phosphorylation under starvation conditions is still possible in ceng1A mutants (Figure 3D, for quantification see Figure 3D’, S3)
Summary
Centaurins comprise a family of multidomain proteins that regulate a variety of cellular processes including cell survival, cell cycle progression, cell migration, receptor and endosome trafficking, gene transcription as well as development of dendrites and synapse conductivity [1,2,3,4]. Centaurins were named after the centaurs of Greek mythology due to their chimeric protein domain architecture They contain a pleckstrin homology (PH) domain mediating membrane recruitment and a GTPase-activating (GAP) domain catalyzing hydrolysis of GTP on ADP-ribosylation factor (Arf) proteins. Members of the Centaurin gamma subfamily harbor an intrinsic GTPase domain whose activity can be modulated by the GAP domain, enabling them to act as molecular switches [7]
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