Selective gene activation by spatial segregation of insulin receptor B signaling.
Insulin exerts pleiotropic effects at the cellular level. Signaling via the two isoforms of the insulin receptor (IR) may explain the activation of different signaling cascades, while it remains to be explored how selectivity is achieved when utilizing the same IR isoform. We now demonstrate that insulin-stimulated transcription of c-fos and glucokinase genes is activated simultaneously in the insulin-producing beta-cell via IR-B localized in different cellular compartments. Insulin activates the glucokinase gene from plasma membrane-standing IR-B, while c-fos gene activation is dependent on clathrin-mediated IR-B-endocytosis and signaling from early endosomes. Moreover, glucokinase gene up-regulation requires the integrity of the juxtamembrane IR-B NPEY-motif and signaling via PI3K-C2alpha-like/PDK1/PKB, while c-fos gene activation requires the intact C-terminal YTHM-motif and signaling via PI3K Ia/Shc/MEK1/ERK. By using IR-B as an example it is thus possible to demonstrate how spatial segregation allows simultaneous and selective signaling via the same receptor isoform in the same cell.
Uhles
Sabine
S
The Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, S-171 76 Stockholm, Sweden.
Moede
Tilo
T
Leibiger
Barbara
B
Berggren
Per-Olof
PO
Leibiger
Ingo B
IB
D001483:Base Sequence; D002460:Cell Line; D017931:DNA Primers; D005786:Gene Expression Regulation; D016762:Genes, fos; D006801:Humans; D007515:Islets of Langerhans / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering; D011972:Receptor, Insulin / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D015533:Transcriptional Activation
D017931:DNA Primers; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D011972:Receptor, Insulin; D020928:Mitogen-Activated Protein Kinases