Abstract
IA-2 (insulinoma-associated protein 2), a major autoantigen in type 1 diabetes, is a receptor-tyrosine phosphatase-like protein associated with the membrane of secretory granules of neural and endocrine-specific cells. Loss of IA-2 activity in the mouse results in reduced insulin release and additional phenotypes, consistent with a general effect on neurosecretion and hormone release. To gain further insight into the cellular mechanisms of IA-2 function, we have studied the Caenorhabditis elegans homolog, CeIA-2 encoded by the ida-1 gene. Using two independent putative null alleles of ida-1, we demonstrate that animals lacking CeIA-2 activity are viable and exhibit subtle defects. Genetic studies of mutants in ida-1 and several genes involved in neurosecretory vesicle cargo release and signaling highlight two roles for CeIA-2. First, CeIA-2 has a specific and novel genetic interaction with UNC-31/CAPS, a protein that has been shown in other systems to regulate dense-core vesicle cargo release. Second, loss of CeIA-2 activity enhances weak alleles in the insulin-like signaling pathway. These results suggest that CeIA-2 may be an important factor in dense-core vesicle cargo release with parallels to insulin signaling in mammals.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Aldicarb / pharmacology
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Alleles
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Animals
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Autoantigens
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Caenorhabditis elegans / drug effects
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Caenorhabditis elegans / physiology*
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Caenorhabditis elegans Proteins / genetics
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Caenorhabditis elegans Proteins / metabolism*
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Caenorhabditis elegans Proteins / physiology*
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Calcium-Binding Proteins / metabolism*
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Drug Resistance / genetics
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Gene Expression Regulation / physiology
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Green Fluorescent Proteins
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Luminescent Proteins / genetics
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Membrane Glycoproteins / biosynthesis
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Membrane Glycoproteins / genetics
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Membrane Glycoproteins / physiology*
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Membrane Proteins / genetics
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Membrane Proteins / physiology*
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Motor Activity / genetics
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Nerve Tissue Proteins / biosynthesis
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Neurosecretion / genetics
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Neurosecretion / physiology*
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Phenotype
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Protein Tyrosine Phosphatase, Non-Receptor Type 1
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Protein Tyrosine Phosphatases / genetics
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Protein Tyrosine Phosphatases / physiology*
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Receptor-Like Protein Tyrosine Phosphatases, Class 8
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Recombinant Fusion Proteins / biosynthesis
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Recombinant Fusion Proteins / genetics
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Signal Transduction / genetics
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Signal Transduction / physiology
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Synaptic Transmission / genetics
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Synaptic Vesicles / metabolism
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Synaptotagmins
Substances
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Autoantigens
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Caenorhabditis elegans Proteins
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Calcium-Binding Proteins
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Luminescent Proteins
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Membrane Glycoproteins
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Membrane Proteins
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Nerve Tissue Proteins
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Recombinant Fusion Proteins
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UNC-31 protein, C elegans
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Synaptotagmins
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Green Fluorescent Proteins
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Aldicarb
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IDA-1 protein, C elegans
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Protein Tyrosine Phosphatase, Non-Receptor Type 1
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Protein Tyrosine Phosphatases
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Ptprn protein, mouse
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Receptor-Like Protein Tyrosine Phosphatases, Class 8