PIKI-1, a class II PI 3-kinase, functions in endocytic trafficking.
Abstract — Entities Highlighted
Gene/ProteinChemicalDiseasePhenotypeAnatomyDev. Stage
Cellular membrane trafficking, including endocytosis and exocytosis, is a complex process coordinated by trafficking-associated proteins, cargo molecules, the cytoskeleton, and membrane lipids. The NIMA-related kinases NEKL-2 (human NEK8/9) and NEKL-3 (human NEK6/7) are conserved regulators of membrane trafficking in Caenorhabditis elegans that are required for the completion of molting. Using a genetic approach, we isolated reduction-of-function mutations in piki-1 that suppress nekl-associated molting defects. piki-1 encodes the sole predicted C. elegans Class II PI 3-kinase (PI3K), a relatively understudied class of lipid modifiers that contribute to the production of PI 3-phosphate (PI(3)P) and PI 3,4-bisphosphate (PI(3,4)P2). Using genetically encoded lipid sensors, we found that PIKI-1 was responsible for the production of PI(3,4)P2 in the C. elegans epidermis but played only a minor role in contributing to PI(3)P levels. Consistent with this, both PI(3,4)P2 and PIKI-1 partially colocalized to early endosomes, and reduction of PIKI-1 affected the size and protein composition of early endosomal compartments marked by RAB-5, EEA-1, and SNX-1. Reduced PIKI-1 also led to increased tubulation of endosomal compartments associated with recycling or the degradation of cellular debris. In contrast to studies using mammalian cell culture, PIKI-1 was largely dispensable for clathrin-mediated endocytosis in the worm epidermis, a polarized epithelium. Notably, reduction of PIKI-1 function mitigated defects in early endosomes associated with the depletion of NEKL-2. We propose that reduction of PIKI-1 function may suppress nekl molting defects by partially restoring endocytic trafficking function within a subset of compartments, including the early endosome. We also show that inhibition of HIPR-1, an ortholog of the mammalian PI(3,4)P₂-binding proteins, HIP1 and HIPR1, suppresses nekl molting defects, consistent with a model that loss of PIKI-1 alters the binding of endocytic regulators in a manner that partially compensates for the loss of NEKL-2 activity.
Relation Network
Specialists Used
deepseek: 65gene_gene: 9gene_expression: 3
All Extracted Relations (151)
| Entity 1 | Relation | Entity 2 | Confidence | Specialist | Direction |
|---|---|---|---|---|---|
| PIKI-1 | regulation | EEA-1 | 100% | gene_gene | supports |
| RAB-5 | regulation | SNX-1 | 100% | gene_gene | supports |
| PIKI-1 | regulation | NEKL-2 | 100% | gene_gene | supports |
| HIPR-1 | regulation | PIKI-1 | 100% | gene_gene | supports |
| HIPR-1 | regulation | NEKL-2 | 100% | gene_gene | supports |
| PIKI-1 | regulation | NEKL-2 | 100% | gene_gene | supports |
| EEA-1 | regulation | SNX-1 | 100% | gene_gene | supports |
| NEKL-2 | regulation | NEKL-3 | 99% | gene_gene | supports |
| piki-1 | regulation | piki-1 | 98% | gene_gene | supports |
| PIKI-1 | expressed in | epidermis | 98% | gene_expression | supports |
| NEK8/9 | binding | NEK6/7 | 97% | — | supports |
| NEKL-2 | binding | NEK8/9 | 96% | — | supports |
| NEKL-2 | binding | NEKL-3 | 96% | — | supports |
| NEKL-2 | binding | NEK6/7 | 96% | — | supports |
| NIMA-related kinases | binding | NEKL-2 | 96% | — | supports |
| NEKL-3 | binding | NEK6/7 | 96% | — | supports |
| NEK8/9 | binding | NEKL-3 | 96% | — | supports |
| PI 3-phosphate | binding | PI 3,4-bisphosphate | 94% | — | supports |
| NIMA-related kinases | binding | NEK6/7 | 94% | — | supports |
| NEKL-2 | binding | membrane trafficking | 93% | — | supports |
| NEKL-3 | binding | membrane trafficking | 93% | — | supports |
| NEK8/9 | binding | membrane trafficking | 92% | — | supports |
| NIMA-related kinases | binding | NEKL-3 | 91% | — | supports |
| NIMA-related kinases | binding | NEK8/9 | 91% | — | supports |
| PI 3-phosphate | binding | PI(3)P | 91% | — | supports |
| mol | binding | ting | 90% | — | supports |
| NEK6/7 | binding | membrane trafficking | 90% | — | supports |
| lipid | binding | PI 3-phosphate | 90% | — | supports |
| PI 3,4-bisphosphate | binding | PI(3,4)P2 | 89% | — | supports |
| C. elegans | binding | Class II PI 3-kinase | 89% | — | supports |
| PI 3-phosphate | binding | PI(3,4)P2 | 89% | — | supports |
| PI(3)P | binding | PI 3,4-bisphosphate | 88% | — | supports |
| PI(3)P | binding | PI(3,4)P2 | 88% | — | supports |
| NEK6/7 | binding | mol | 88% | — | supports |
| membrane trafficking | binding | mol | 88% | — | supports |
| PIKI-1 | not expressed in | epithelium | 87% | gene_expression | refutes |
| NEK6/7 | binding | ting | 86% | — | supports |
| membrane trafficking | binding | ting | 86% | — | supports |
| PIKI-1 | regulates | endocytic trafficking | 85% | deepseek | supports |
| HIPR-1 | binding | PI(3,4)P2 | 85% | deepseek | supports |
| PIKI-1 | regulates | endocytic regulators | 85% | deepseek | supports |
| PIKI-1 | genetic interaction | NEKL-2 | 85% | deepseek | supports |
| PIKI-1 | positively regulates | phagosome clearance | 85% | deepseek | supports |
| PIKI-1 | positively regulates | PI(3)P | 85% | deepseek | supports |
| TAT-1 | regulates | membrane trafficking | 85% | deepseek | supports |
| PIKI-1 | causes phenotype | molting defects | 85% | deepseek | supports |
| PIKI-1 | positively regulates | PI(3,4)P2 | 85% | deepseek | supports |
| PIKI-1 | expressed in | early endosome | 85% | deepseek | supports |
| PIKI-1 | expressed in | clathrin-coated pits | 85% | deepseek | supports |
| PIKI-1 | positively regulates | RAB-5 | 85% | deepseek | supports |
| PIKI-1 | positively regulates | EEA-1 | 85% | deepseek | supports |
| PIKI-1 | negatively regulates | SNX-1 | 85% | deepseek | refutes |
| PIKI-1 | regulates | TGN-38 | 85% | deepseek | supports |
| PI(3,4)P2 | expressed in | early endosome | 85% | deepseek | supports |
| PIKI-1 | positively regulates | AMAN-2 | 85% | deepseek | supports |
| PIKI-1 | positively regulates | LGG-1 | 85% | deepseek | supports |
| PIKI-1 | genetic interaction | NEKL-2 | 85% | deepseek | supports |
| PIKI-1 | genetic interaction | NEKL-3 | 85% | deepseek | supports |
| PIKI-1 | negatively regulates | NEKL-2 | 85% | deepseek | refutes |
| PIKI-1 | associated with | NEKL-3 | 85% | deepseek | supports |
| PIKI-1 | positively regulates | PI(4)P | 85% | deepseek | supports |
| PIKI-1 | binding | PI(4,5)P2 | 85% | deepseek | supports |
| PIKI-1 | binding | PI(3,4,5)P3 | 85% | deepseek | supports |
| PIKI-1 | binding | CLIC-1 | 85% | deepseek | supports |
| PIKI-1 | binding | RAB-5 | 85% | deepseek | supports |
| PIKI-1 | binding | SNX-1 | 85% | deepseek | supports |
| PIKI-1 | positively regulates | PI | 85% | deepseek | supports |
| PIKI-1 | causes phenotype | early endosome defects | 85% | deepseek | supports |
| AGE-1 | positively regulates | PI(3,4,5)P3 | 85% | deepseek | supports |
| INPP-1 | negatively regulates | PI(3,4,5)P3 | 85% | deepseek | refutes |
| NEKL-2 | expressed in | early endosome | 85% | deepseek | supports |
| NEKL-3 | expressed in | late endosome | 85% | deepseek | supports |
| NEKL-2 | negatively regulates | RAB-5 | 85% | deepseek | refutes |
| NEKL-3 | negatively regulates | CHC-1 | 85% | deepseek | refutes |
| PI(3)P | expressed in | early endosome | 85% | deepseek | supports |
| PI(4,5)P2 | positively regulates | clathrin-mediated endocytosis | 85% | deepseek | supports |
| class III PI3Ks | positively regulates | PI(3)P | 85% | deepseek | supports |
| class I PI3Ks | positively regulates | PI(3,4,5)P3 | 85% | deepseek | supports |
| SNX-1 | binding | PI(3)P | 85% | deepseek | supports |
| 2xFYVE | binding | PI(3)P | 85% | deepseek | supports |
| 2xTAPP1 | binding | PI(3,4)P2 | 85% | deepseek | supports |
| PH PLC δ | binding | PI(4,5)P2 | 85% | deepseek | supports |
| BTK PH | binding | PI(3,4,5)P3 | 85% | deepseek | supports |
| NEKL-2 | genetic interaction | NEKL-3 | 85% | deepseek | supports |
| MLT-2 | binding | NEKL-2 | 85% | deepseek | supports |
| MLT-3 | binding | NEKL-2 | 85% | deepseek | supports |
| MLT-4 | binding | NEKL-2 | 85% | deepseek | supports |
| NEKL-2 | positively regulates | molting | 85% | deepseek | supports |
| NEKL-3 | positively regulates | molting | 85% | deepseek | supports |
| piki-1 | negatively regulates | nekl-associated molting defects | 85% | deepseek | refutes |
| PIKI-1 | positively regulates | PI(3,4)P2 | 85% | deepseek | supports |
| PIKI-1 | positively regulates | PI(3)P | 85% | deepseek | supports |
| PI(3,4)P2 | expressed in | early endosomes | 85% | deepseek | supports |
| PIKI-1 | expressed in | early endosomes | 85% | deepseek | supports |
| PIKI-1 | regulates | early endosomal compartments | 85% | deepseek | supports |
| PIKI-1 | associated with | RAB-5 | 85% | deepseek | supports |
| PIKI-1 | associated with | EEA-1 | 85% | deepseek | supports |
| PIKI-1 | associated with | SNX-1 | 85% | deepseek | supports |
| PIKI-1 | regulates | endosomal compartments | 85% | deepseek | supports |
| PIKI-1 | negatively regulates | clathrin-mediated endocytosis | 85% | deepseek | refutes |
| PIKI-1 | negatively regulates | NEKL-2 | 85% | deepseek | refutes |
| piki-1 | negatively regulates | nekl molting defects | 85% | deepseek | refutes |
| HIPR-1 | negatively regulates | nekl molting defects | 85% | deepseek | refutes |
| PIKI-1 | not expressed in | epidermis | 85% | gene_expression | refutes |
| NIMA-related kinases | binding | membrane trafficking | 83% | — | supports |
| piki-1 | binding | Class II PI 3-kinase | 83% | — | supports |
| Class II PI 3-kinase | binding | PI3K | 83% | — | supports |
| C. elegans | binding | PI3K | 83% | — | supports |
| PI3K | binding | lipid | 82% | — | supports |
| piki-1 | binding | C. elegans | 81% | — | supports |
| piki-1 | binding | piki-1 | 81% | — | supports |
| PIKI-1 | independent of | clathrin-mediated endocytosis | 80% | — | supports |
| early endosomes | associated with | NEKL-2 | 80% | — | supports |
| HIPR-1 | ortholog of | PI(3,4)P₂-binding proteins | 80% | — | supports |
| molting defects | binding | C. elegans | 80% | — | supports |
| piki-1 | binding | molting defects | 80% | — | supports |
| piki-1 | binding | nekl-associated | 78% | — | supports |
| Cellular membrane trafficking | binding | trafficking-associated proteins | 73% | — | supports |
| nekl-associated | binding | piki-1 | 72% | — | supports |
| nekl-associated | binding | molting defects | 71% | — | supports |
| HIPR1 | suppresses | nekl | 70% | — | supports |
| endocytosis | binding | trafficking-associated proteins | 66% | — | supports |
| exocytosis | binding | trafficking-associated proteins | 66% | — | supports |
| molting defects | binding | piki-1 | 64% | — | supports |
| PI(3,4)P2 | binding | EEA-1 | 62% | — | supports |
| PIKI-1 | binding | EEA-1 | 62% | — | supports |
| PIKI-1 | binding | RAB-5 | 60% | — | supports |
| HIP1 | binding | HIPR1 | 60% | — | supports |
| piki-1 | negatively regulates | piki-1 | 59% | — | supports |
| PI(3,4)P2 | binding | RAB-5 | 58% | — | supports |
| PIKI-1 | binding | SNX-1 | 56% | — | supports |
| NEKL-2 | required for | NEKL-3 | 56% | — | supports |
| HIPR-1 | negatively regulates | PIKI-1 | 56% | — | supports |
| PI(3,4)P2 | binding | SNX-1 | 56% | — | supports |
| PIKI-1 | negatively regulates | thin | 54% | — | uncertain |
| Cellular membrane trafficking | binding | endocytosis | 54% | — | supports |
| Cellular membrane trafficking | binding | exocytosis | 51% | — | supports |
| PI(3,4)P₂-binding proteins | binding | HIPR1 | 51% | — | supports |
| PI(3,4)P₂-binding proteins | binding | HIP1 | 50% | — | supports |
| PI(3,4)P2 | binding | PIKI-1 | 49% | — | supports |
| HIPR1 | binding | PIKI-1 | 49% | — | supports |
| PIKI-1 | biomarker | NEKL-2 | 48% | — | supports |
| HIP1 | binding | PIKI-1 | 47% | — | supports |
| RAB-5 | binding | SNX-1 | 46% | — | supports |
| RAB-5 | binding | EEA-1 | 45% | — | supports |
| HIPR-1 | binding | HIPR1 | 43% | — | supports |
| HIPR-1 | binding | HIP1 | 43% | — | supports |
| PIKI-1 | binding | NEKL-2 | 39% | — | supports |
| PIKI-1 | biomarker | nekl | 37% | — | supports |
| nekl | biomarker | endocytic trafficking | 36% | — | supports |
| PIKI-1 | biomarker | endocytic trafficking | 33% | — | supports |