Linked Life Data

21071436

Source:http://linkedlifedata.com/resource/pubmed/id/21071436

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
2
pubmed:dateCreated
2011-1-10
pubmed:abstractText
Inositol 1,4,5-trisphosphate (IP(3)) receptors (IP(3)Rs) are large, ubiquitously expressed, endoplasmic reticulum membrane proteins that form tetrameric IP(3) and Ca(2+)-gated Ca(2+) channels. Endogenous IP(3)Rs provide very appealing tools for studying the ubiquitin-proteasome pathway in intact mammalian cells because, upon activation, they are rapidly ubiquitinated and degraded. Using mass spectrometry, we previously examined the ubiquitination of IP(3)R1 in ?T3-1 pituitary gonadotrophs and found that IP(3)R1 ubiquitination is highly complex, with receptors being modified at multiple sites by monoubiquitin and polyubiquitin chains formed through both Lys-48 and Lys-63 linkages (Sliter, D. A., Kubota, K., Kirkpatrick, D. S., Alzayady, K. J., Gygi, S. P., and Wojcikiewicz, R. J. H. (2008) J. Biol. Chem. 283, 35319-35328). Here, we have extended these studies to determine whether IP(3)R2 and IP(3)R3 are similarly modified and if ubiquitination is cell type-dependent. Using mass spectrometry and linkage-specific ubiquitin antibodies, we found that all IP(3)R types are subject to ubiquitination at approximately the same locations and that, independent of cell type, IP(3)Rs are modified by monoubiquitin and Lys-48- and Lys-63-linked ubiquitin chains, although in differing proportions. Remarkably, the attached Lys-48- and Lys-63-linked ubiquitin chains are homogeneous and are segregated to separate IP(3)R subunits, and Lys-48-linked ubiquitin chains, but not Lys-63-linked chains, are required for IP(3)R degradation. Together, these data provide unique insight into the complexities of ubiquitination of an endogenous ubiquitin-proteasome pathway substrate in unperturbed mammalian cells. Importantly, although Lys-48-linked ubiquitin chains appear to trigger proteasomal degradation, the presence of Lys-63-linked ubiquitin chains suggests that ubiquitination of IP(3)Rs may have physiological consequences beyond signaling for degradation.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Jan
pubmed:issn
1083-351X
pubmed:author
pubmed:issnType
Electronic
pubmed:day
14
pubmed:volume
286
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
1074-82
pubmed:meshHeading
pubmed-meshheading:21071436-Amino Acid Sequence, pubmed-meshheading:21071436-Animals, pubmed-meshheading:21071436-Calcium Channels, pubmed-meshheading:21071436-Cell Line, Tumor, pubmed-meshheading:21071436-Fibroblasts, pubmed-meshheading:21071436-Humans, pubmed-meshheading:21071436-Inositol 1,4,5-Trisphosphate Receptors, pubmed-meshheading:21071436-Lysine, pubmed-meshheading:21071436-Mice, pubmed-meshheading:21071436-Molecular Sequence Data, pubmed-meshheading:21071436-Neuroblastoma, pubmed-meshheading:21071436-Pancreatic Neoplasms, pubmed-meshheading:21071436-Pituitary Gland, pubmed-meshheading:21071436-Proteasome Endopeptidase Complex, pubmed-meshheading:21071436-Protein Structure, Tertiary, pubmed-meshheading:21071436-Rats, pubmed-meshheading:21071436-Receptors, Cytoplasmic and Nuclear, pubmed-meshheading:21071436-Ubiquitin, pubmed-meshheading:21071436-Ubiquitination
pubmed:year
2011
pubmed:articleTitle
Activated inositol 1,4,5-trisphosphate receptors are modified by homogeneous Lys-48- and Lys-63-linked ubiquitin chains, but only Lys-48-linked chains are required for degradation.
pubmed:affiliation
Department of Pharmacology, State University of New York Upstate Medical University, Syracuse, New York 13210, USA.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural