PI3K Signaling in Caenorhabditis elegans
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PI3K Signaling in Caenorhabditis elegans

PI3Ks (Phosphoinositide 3-Kinases) are an important type of lipid kinase that form a large evolutionarily conserved family of enzymes that specifically phosphorylate inositol phospholipids at the D-3 position of the inositol ring. The C. elegans (Caenorhabditis elegans) PI3K is required for functional membrane trafficking machinery (Ref.1). C. elegans PI3K adaptor subunit aap-1 (Phosphoinositide 3-Kinase age-1 Adapter Subunit-58.5 KD) shares moderate sequence similarity with the p50/p55 adaptor subunits of their vertebrate and Drosophila counterparts. C. elegans PI3K also contains age-1 (Ageing Alteration-age-1), a homolog of vertebrate p110 catalytic subunits of PI3K (Ref.2 & 3).

An insulin receptor-like signaling pathway regulates C. elegans metabolism, development and longevity. The C. elegans daf-2 (Abnormal Dauer Formation-daf-2-207.1 KD/Insulin Receptor Homolog/Regulator of Lifespan and Dauer Formation) receptor utilizes ist-1 (Insulin Receptor SubsTrate Homolog-113.5 KD) and aap-1, to activate downstream signaling pathways. These genes transduce signals from the daf-2 receptor to age-1. Insulin-Like Ligands activate daf-2, triggering tyrosine phosphorylation on YXXM PI3K target sites in the daf-2 COOH terminus and in ist-1. Both aap-1 and ist-1 are required for full daf-2 pathway signaling. Thus aap-1 and ist-1 potentiate signaling downstream from the daf-2 receptor (Ref.2 & 3). Inactivation of the insulin receptor homolog daf-2, the PI3K, or the akt-1 (Akt Kinase-62.7 KD) and akt-2 (Akt Kinase-55.8 kD) kinases causes a developmental arrest at the dauer stage. A pdk-1 (3-Phophoinositide-Dependent Protein Kinase-71.4 KD) homolog is necessary and sufficient to transduce PI3K signals that regulate diapause in C. elegans. pdk-1 activity is both necessary and sufficient to propagate PI3K signals in the daf-2 insulin receptor-like signaling pathway. The major function of C. elegans pdk-1 is to transduce signals from PI3K to akt-1 and akt-2. In C. elegans, a signal transduction cascade from the daf-2 receptor to the daf-16 (Abnormal Dauer Formation-daf-16-57.9 KD) regulates the process of metabolism, development and longevity. Reduction of signaling through the daf-2 insulin receptor-like signaling pathway causes the animals to arrest at a reversible diapause stage known as the dauer larval stage. Dauer larvae do not feed or reproduce and their metabolism are shifted to energy storage (Ref.4).

Activation of PI3K generates 3-Phosphoinositides, such as PtdIns(3,4)P2 (Phosphatidylinositol 3,4-bisphosphate) and PIP3 (Phosphatidylinositol 3,4,5-trisphosphate), which act as second messengers in signal transduction cascades because their levels rise rapidly in response to growth factor signaling. PtdIns(3,4)P2 and/or PIP3 bind to the pleckstrin homology domain of akt-1/akt-2 and are required for its activation. Phosphoinositide binding causes akt-1/akt-2 to undergo a conformational change that makes two phosphorylation sites accessible to the pertinent kinases (Ref.5). pdk-1 phosphorylates the Thr-308 (Threonine-308) site on akt-1/akt-2 in a phosphoinositide dependent manner. C. elegans akt-1 has both the Thr-308 and Ser-473 (Serine-473) equivalent phosphorylation sites whereas akt-2 has only the Thr-308 equivalent site, raising the possibility that these proteins are differentially regulated. pdk-1 antagonizes daf-16 by activating akt-1 and akt-2. The phosphoinositides generated by PI3K activate pdk-1 and, in cooperation with phosphorylation by pdk-1 and pdk-2 (3-Phophoinositide-Dependent Protein Kinase-2), activate akt-1 and akt-2. akt-1 and akt-2 negatively regulate the daf-16 transcription factor, possibly via direct phosphorylation of daf-16. The C. elegans daf-16 is active when insulin receptor-like signaling is decreased. Un-phosphorylated daf-16 function to activate genes necessary for dauer arrest, metabolism, and increased life span or could repress genes necessary for reproductive growth. The daf-2, PI3K, pdk-1, akt-1/akt-2, the daf-18 (Abnormal Dauer Formation-daf18-110.3 KD/PTEN Phosphatidylinositol 3 Phosphatase) and the daf-16 transcription factor act in the same cell to transduce signals from Insulin-Like Ligand to transcriptional outputs regulated by daf-16 in the nucleus. It has not yet been determined if these genes in fact act in the same cells to regulate dauer formation (Ref.4).

The C. elegans akt homologs akt-1 and akt-2 function to antagonize the daf-16 transcription factor and repress the metabolic shift and growth arrest associated with the dauer stage. Both akt-1 and akt-2 transduce daf-2 signals because both gene activities are decreased to cause dauer arrest. A major distinction between akt-1 and akt-2 is that akt-1 bears two phosphorylation sites, the Thr-308 and Ser-473, whereas akt-2 only has the Thr-308 phosphorylation site. akt-1 couples to a pdk-2-like kinase whereas akt-2 cannot do so. Under normal growth conditions, an Insulin-Like Ligand binds to the daf-2 insulin receptor kinase inducing autophosphorylation and recruitment of PI3K. A parallel pathway (or pathways) from the daf-2 is also activated. The akt-1 and akt-2 kinases, as well as molecules from the parallel pathway, negatively regulate daf-16 activity, possibly via phosphorylation. Phosphorylated daf-16, inactive, functions to activate genes required for reproductive growth and metabolism, or repress genes required for dauer arrest and energy storage. Other signaling molecules that are activated by daf-2 converge downstream of PI3K (e.g., on daf-16 or akt-1/akt-2) for proper regulation of metabolism and life span. Under dauer-inducing conditions, daf-2, PI3K, akt-1/akt-2 and other signaling pathways from daf-2 are inactive and therefore daf-16 is active, because it is under-phosphorylated. Active daf-16 either represses genes required for reproductive growth and metabolism or activates genes necessary for dauer arrest and energy storage. The daf-16 interacts with the daf-3 (Abnormal Dauer Formation-daf-3-90.9 KD/SMAD4 (Similar to Mothers Against Decapentaplegic-4)), daf-8 (Abnormal Dauer Formation-daf-8), or daf-14(Abnormal Dauer Formation-daf-14-32.7 KD/ Dauer Larva Development Regulatory SMAD Protein) proteins to integrate converging TGF-Beta-like neuroendocrine signals with Insulin-like. daf-16 forms a complex with the daf-3 SMAD protein under dauer-inducing conditions to regulate these downstream genes and akt-1/akt-2 phosphorylation of daf-16 inhibits the formation of a SMAD/Fork head complex during reproductive development (Ref.6).

TGF-Beta (Transforming Growth Factor-Beta) related signaling pathway functions in parallel to the daf-2 insulin receptor-like signaling pathway to regulate dauer formation (Ref.4). Insulin-like and TGF-Beta neuroendocrine signals regulate whether animals arrest at the dauer stage or grow to reproductive adults. The TGF-Beta-Like molecule daf-7 (Abnormal Dauer Formation-daf-7-39.5 KD/ Dauer Larva Development Regulatory Growth Factor/Transforming Growth Factor-Beta Superfamily Member Expressed in Chemosensory Neurons) is a neuroendocrine signal that represses dauer arrest and its expression is regulated by dauer-inducing pheromone (Ref.6). In C. elegans, the TGF-Beta-Like Type-II receptor daf-4 (Abnormal Dauer Formation-daf-4-84.4 KD/Activin/BMP Cell-Surface Receptor) is required for two distinct signaling pathways. In association with the Type-I Receptor daf-1 (Abnormal Dauer Formation-daf-1/ Cell-Surface Receptor daf-1-74.9 KD), it functions in the dauer pathway. In addition, it is also required for body size determination and male tail patterning, roles which do not require daf-1. In C. elegans, the daf-7 gene encodes a divergent ligand and is involved in dauer formation (Ref.7).