Abstract
We examined the signaling function of the IGF-II/mannose 6-phosphate receptor (IGF-IIR) by transfecting IGF-IIR cDNAs into COS cells, where adenylyl cyclase (AC) was inhibited by transfection of constitutively activated G alpha i cDNA (G alpha i2Q205L). In cells transfected with IGF-IIR cDNA, IGF-II decreased cAMP accumulation promoted by cholera toxin or forskolin. This effect of IGF-II was not observed in untransfected cells or in cells transfected with IGF-IIRs lacking Arg2410-Lys2423. Thus, IGF-IIR, through its cytoplasmic domain, mediates the Gi-linked action of IGF-II in living cells. We also found that IGF-IIR truncated with C-terminal 28 residues after Ser2424 caused G beta gamma-dominant response of AC in response to IGF-II by activating Gi. Comparison with the G alpha i-dominant response of AC by intact IGF-IIR suggests that the C-terminal 28-residue region inactivates G beta gamma. This study not only provides further evidence that IGF-IIR has IGF-II-dependent signaling function to interact with heteromeric G proteins with distinct roles by different cytoplasmic domains, it also suggests that IGF-IIR can separate and sequestrate the G alpha and G beta gamma signals following Gi activation.
Highlights
We examined the signaling function of the IGF-II/mannose 6-phosphate receptor (IGF-IIR) by transfecting IGF-IIR cDNAs into COS cells, where adenylyl cyclase (AC) was inhibited by transfection of constitutively activated G␣i cDNA (G␣i2Q205L)
This study provides further evidence that IGFIIR has IGF-II-dependent signaling function to interact with heteromeric G proteins with distinct roles by different cytoplasmic domains, it suggests that IGFIIR can separate and sequestrate the G␣ and G␥ signals following Gi activation
To the extreme C terminus of IGF-IIR, we assigned a novel function of inactivating G␥, which is another component of heteromeric G proteins
Summary
We examined the signaling function of the IGF-II/mannose 6-phosphate receptor (IGF-IIR) by transfecting IGF-IIR cDNAs into COS cells, where adenylyl cyclase (AC) was inhibited by transfection of constitutively activated G␣i cDNA (G␣i2Q205L). In cells transfected with intact IGF-IIR cDNA, IGF-II significantly impaired the CTX-stimulated AC activity in a dose-dependent manner (Fig. 1C). These data indicate that IGF-II triggers the signaling function of IGF-IIR and couples it to the G␣i/AC system in living cells.
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