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The Journal of Neuroscience, March 24, 2004, 24(12):3115-3124; doi:10.1523/JNEUROSCI.0101-04.2004
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Cellular/Molecular
Insulinoma-Associated Protein IA-2, a Vesicle Transmembrane Protein, Genetically Interacts with UNC-31/CAPS and Affects Neurosecretion in Caenorhabditis elegans
Tao Cai,1 Tetsunari Fukushige,2 Abner L. Notkins,1 andMichael Krause2 1Experimental Medicine Section, Oral Infection and Immunity Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland 20892, and 2Section of Developmental Biology, Laboratory of Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892
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.
Key words: autoantigen; diabetes; insulin; synaptic transmission; dense core vesicle; protein tyrosine phosphatase; PTP; aldicarb; dauer; C. elegans
Received July 22, 2003; revised February 1, 2004; accepted February 2, 2004.
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