Selective recruitment of G protein-coupled receptor kinases (GRKs) controls signaling of the insulin-like growth factor 1 receptor

Apr 18, 2012Proceedings of the National Academy of Sciences of the United States of America

Selective control of insulin-like growth factor 1 receptor signaling by specific regulatory proteins

AI simplified

Circadian Biology on OpenScience ↗PubMed ↗DOI ↗

Abstract

Lowering GRK5/6 abolishes IGF-1-mediated ERK and AKT activation.

Inhibition of GRK2 increases ERK activation while partially inhibiting AKT signaling.
Overexpression of GRK6 enhances β-arrestin-mediated ERK signaling, whereas GRK2 diminishes it.
GRK2 decreases and GRK6 enhances ligand-induced degradation of IGF-1R.
GRK2 and GRK6 interact with IGF-1R and increase its serine phosphorylation, promoting β-arrestin1 association.
The association of β-arrestin with IGF-1R is transient for GRK2 and stable for GRK6.
Serines 1248 and 1291 of IGF-1R are key phosphorylation sites affecting signaling and degradation influenced by GRK isoforms.

AI simplified

β-Arrestins are multifunctional proteins that play central roles in G protein-coupled receptor (GPCR) trafficking and signaling. β-Arrestin1 is also recruited to the insulin-like growth factor-1 receptor (IGF-1R), a receptor tyrosine kinase (RTK), mediating receptor degradation and signaling. Because GPCR phosphorylation by GPCR-kinases (GRKs) governs interactions of the receptors with β-arrestins, we investigated the regulatory roles of the four widely expressed GRKs on IGF-1R signaling/degradation. By suppressing GRK expression with siRNA, we demonstrated that lowering GRK5/6 abolishes IGF1-mediated ERK and AKT activation, whereas GRK2 inhibition increases ERK activation and partially inhibits AKT signaling. Conversely, β-arrestin-mediated ERK signaling is enhanced by overexpression of GRK6 and diminished by GRK2. Similarly, we demonstrated opposing effects of GRK2 and -6 on IGF-1R degradation: GRK2 decreases whereas GRK6 enhances ligand-induced degradation. GRK2 and GRK6 coimmunoprecipitate with IGF-1R and increase IGF-1R serine phosphorylation, promoting β-arrestin1 association. Using immunoprecipitation, confocal microscopy, and FRET analysis, we demonstrated β-arrestin/IGF-1R association to be transient for GRK2 and stable for GRK6. Using bioinformatic studies we identified serines 1248 and 1291 as the major serine phosphorylation sites of the IGF-1R, and subsequent mutation analysis demonstrated clear effects on IGF-1R signaling and degradation, mirroring alterations by GRKs. Targeted mutation of S1248 recapitulates GRK2 modulation, whereas S1291 mutation resembles GRK6 effects on IGF-1R signaling/degradation, consistent with GRK isoform-specific serine phosphorylation. This study demonstrates distinct roles for GRK isoforms in IGF-1R signaling through β-arrestin binding with divergent functional outcomes.

Full Text

Full text is available at the source.

View full text ↗

Selective recruitment of G protein-coupled receptor kinases (GRKs) controls signaling of the insulin-like growth factor 1 receptor

Abstract

Full Text

You found one interesting study. We’ll send the next 7.

what lands in your inbox each week:

Recent issues from the circadian biology brief

Abstract

Full Text

Related papers

You found one interesting study. We’ll send the next 7.

what lands in your inbox each week:

Recent issues from the circadian biology brief