A TrkB/insulin receptor-related receptor chimeric receptor induces PC12 cell differentiation and exhibits prolonged activation of mitogen-activated protein kinase.
Insulin receptor-related receptor (IRR), an orphan receptor in the insulin receptor (IR) family of receptor tyrosine kinases, is primarily localized to neural crest-derived sensory neurons during embryonic development. Expression of IRR closely resembles that of the nerve growth factor receptor, TrkA. To analyze the signaling properties and function of IRR in PC12 cells, a TrkB/IRR hybrid receptor was used. In contrast to IR activation, brain-derived neurotrophic growth factor-mediated activation of the TrkB/IRR receptor resulted in differentiation rather than proliferation. Analysis of cytoplasmic substrates activated by the TrkB/IRR receptor indicates a signaling pathway similar to that of the IR. Mutagenesis studies further show that only TrkB/IRR receptors able to phosphorylate mitogen-activated protein kinase elicit a differentiation response. Our analysis indicates that prolonged kinetics of mitogen-activated protein kinase activation mediated by the TrkB/IRR chimeric receptor correlates with induction to differentiate.
Kelly-Spratt
K S
KS
Center for Developmental Biology, University of Texas Southwestern Medical Center, Dallas 75235-9133, USA.
Klesse
L J
LJ
Merenmies
J
J
Parada
L F
LF
D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D007700:Kinetics; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D016716:PC12 Cells / Q000166:cytology / Q000187:drug effects; D051381:Rats; D011972:Receptor, Insulin / Q000235:genetics / Q000378:metabolism*; D020813:Receptor, trkB / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D013379:Substrate Specificity; D014443:Tyrosine / Q000378:metabolism
D019208:Brain-Derived Neurotrophic Factor; D011993:Recombinant Fusion Proteins; D014443:Tyrosine; D011972:Receptor, Insulin; D020813:Receptor, trkB; C066542:insulin receptor-related receptor; D020928:Mitogen-Activated Protein Kinases