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PMID:15843412

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Citation

Goberdhan, DC, Meredith, D, Boyd, CA and Wilson, C (2005) PAT-related amino acid transporters regulate growth via a novel mechanism that does not require bulk transport of amino acids. Development 132:2365-75

Abstract

Growth in normal and tumour cells is regulated by evolutionarily conserved extracellular inputs from the endocrine insulin receptor (InR) signalling pathway and by local nutrients. Both signals modulate activity of the intracellular TOR kinase, with nutrients at least partly acting through changes in intracellular amino acid levels mediated by amino acid transporters. We show that in Drosophila, two molecules related to mammalian proton-assisted SLC36 amino acid transporters (PATs), CG3424 and CG1139, are potent mediators of growth. These transporters genetically interact with TOR and other InR signalling components, indicating that they control growth by directly or indirectly modulating the effects of TOR signalling. A mutation in the CG3424 gene, which we have named pathetic (path), reduces growth in the fly. In a heterologous Xenopus oocyte system, PATH also activates the TOR target S6 kinase in an amino acid-dependent way. However, functional analysis reveals that PATH has an extremely low capacity and an exceptionally high affinity compared with characterised human PATs and the CG1139 transporter. PATH and potentially other PAT-related transporters must therefore control growth via a mechanism that does not require bulk transport of amino acids into the cell. As PATH is likely to be saturated in vivo, we propose that one specialised function of high-affinity PAT-related molecules is to maintain growth as local nutrient levels fluctuate during development.

Links

PubMed Online version:10.1242/dev.01821

Keywords

Amino Acid Transport Systems/metabolism; Amino Acids/metabolism; Animals; Animals, Genetically Modified; Biological Transport/physiology; Blotting, Western; Cell Growth Processes/genetics; Cell Growth Processes/physiology; Drosophila; Drosophila Proteins/genetics; Drosophila Proteins/metabolism; Gene Expression Regulation, Developmental; In Situ Hybridization; Mutation/genetics; Oocytes/metabolism; Phosphatidylinositol 3-Kinases/genetics; Phosphatidylinositol 3-Kinases/metabolism; Photoreceptor Cells, Invertebrate/cytology; Protein Kinases; Receptor Protein-Tyrosine Kinases/metabolism; Ribosomal Protein S6 Kinases/metabolism; Signal Transduction/physiology; Wing/anatomy & histology; Xenopus

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

DROME:P91656

involved_in

GO:0030307: positive regulation of cell growth

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

DROME:Q8SWT5

involved_in

GO:0030307: positive regulation of cell growth

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

DROME:Q94533

involved_in

GO:0030307: positive regulation of cell growth

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

DROME:PATH

involved_in

GO:0040008: regulation of growth

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

DROME:PATH

involved_in

GO:0003333: amino acid transmembrane transport

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

DROME:PATH

enables

GO:0015171: amino acid transmembrane transporter activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

DROME:C1139

involved_in

GO:0040008: regulation of growth

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

DROME:C1139

involved_in

GO:0003333: amino acid transmembrane transport

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

DROME:C1139

enables

GO:0015171: amino acid transmembrane transporter activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

DROME:FOXO

involved_in

GO:0001745: compound eye morphogenesis

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

See also

References

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