Association of heterotrimeric G(i) with the insulin-like growth factor-I receptor. Release of G(betagamma) subunits upon receptor activation.
The insulin-like growth factor-I receptor (IGF-IR) is a key regulator of cell proliferation and survival. Activation of the IGF-IR induces tyrosine autophosphorylation and the binding of a series of adaptor molecules, thereby leading to the activation of MAPK. It has been demonstrated that pertussis toxin, which inactivates the G(i) class of GTP-binding proteins, inhibits IGF-I-mediated activation of MAPK, and a specific role for G(betagamma) subunits in IGF-I signaling was shown. In the present study, we have investigated the role of heterotrimeric G(i) in IGF-IR signaling in neuronal cells. Pertussis toxin inhibited IGF-I-induced activation of MAPK in rat cerebellar granule neurons and NG-108 neuronal cells. G(alphai) and G(beta) subunits were associated with IGF-IR immunoprecipitates. Similarly, in IGF-IR-null mouse embryo fibroblasts transfected with the human IGF-IR, G(i) was complexed with the IGF-IR. G(alphas) was not associated with the IGF-IR in any cell type. IGF-I induced the release of the G(beta) subunits from the IGF-IR but had no effect on the association of G(alphai). These results demonstrate an association of heterotrimeric G(i) with the IGF-IR and identify a discrete pool of G(betagamma) subunits available for downstream signaling following stimulation with IGF-I.
Hallak
H
H
Department of Pathology, Jefferson Medical College, Philadelphia, Pennsylvania 19107, USA.
Seiler
A E
AE
Green
J S
JS
Ross
B N
BN
Rubin
R
R
D016475:3T3 Cells; D000818:Animals; D004789:Enzyme Activation; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D037342:Pertussis Toxin; D051381:Rats; D017451:Receptors, Somatomedin / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D010566:Virulence Factors, Bordetella / Q000494:pharmacology
D017451:Receptors, Somatomedin; D010566:Virulence Factors, Bordetella; D037342:Pertussis Toxin; D020928:Mitogen-Activated Protein Kinases; D019206:GTP-Binding Protein alpha Subunits, Gi-Go