ArticleThe Journal of biological chemistry2012
Serine phosphorylation of the insulin-like growth factor I (IGF-1) receptor C-terminal tail restrains kinase activity and cell growth.
Article in The Journal of biological chemistry, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed, 30 citations in OpenAlex.
- Article
- The adenovirus E4orf1 protein initiates a feedback loop involving insulin and growth factor receptors, AKT, and NF-κB, leading to abnormal DNA content in infected cells.PLoS pathogens · 2025Article
- The Role of GSK-3β in the Regulation of Protein Turnover, Myosin Phenotype, and Oxidative Capacity in Skeletal Muscle under Disuse Conditions.International journal of molecular sciences · 2021Review
- Defining the epitope of a blood-brain barrier crossing single domain antibody specific for the type 1 insulin-like growth factor receptor.Scientific reports · 2021Article
- Emerging roles of the αC-β4 loop in protein kinase structure, function, evolution, and disease.IUBMB life · 2020Review
- Insulin-like growth factor-binding proteins play a significant role in the molecular response to imatinib in chronic myeloid leukemia patients.Experimental and therapeutic medicine · 2020Article
- Modeling cell line-specific recruitment of signaling proteins to the insulin-like growth factor 1 receptor.PLoS computational biology · 2019Article
- Impact of phosphorylated insulin-like growth factor-1 receptor on the outcome of breast cancer patients and the prognostic value of its alteration during neoadjuvant chemotherapy.Experimental and therapeutic medicine · 2018Article
- How Protein Kinase A Activates Canonical Tyrosine Kinase Signaling Pathways To Promote Granulosa Cell Differentiation.Endocrinology · 2017Article
- Glycogen synthase kinase-3 (GSK3): regulation, actions, and diseases.Pharmacology & therapeutics · 2015Review
- IGF-1 Receptor and Adhesion Signaling: An Important Axis in Determining Cancer Cell Phenotype and Therapy Resistance.Frontiers in endocrinology · 2015Review
- Something old, something new and something borrowed: emerging paradigm of insulin-like growth factor type 1 receptor (IGF-1R) signaling regulation.Cellular and molecular life sciences : CMLS · 2014Review
- Celecoxib inhibits insulin-like growth factor 1 induced growth and invasion in non-small cell lung cancer.Oncology letters · 2013Article
Corrections and comments
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Authors and funding
5 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Insulin-like growth factor I receptor (IGF-1R) signaling is essential for cell, organ, and animal growth. The C-terminal tail of the IGF-1R exhibits regulatory function, but the mechanism is unknown. Here, we show that mutation of Ser-1248 (S1248A) enhances IGF-1R in vitro kinase activity, autophosphorylation, Akt/mammalian target of rapamycin activity, and cell growth. Ser-1248 phosphorylation is mediated by GSK-3β in a mechanism that involves a priming phosphorylation on Ser-1252. GSK-3β knock-out cells exhibit reduced IGF-1R cell surface expression, enhanced IGF-1R kinase activity, and signaling. Examination of crystallographic structures of the IGF-1R kinase domain revealed that the (1248)SFYYS(1252) motif adopts a conformation tightly packed against the kinase C-lobe when Ser-1248 is in the unphosphorylated state that favors kinase activity. S1248A mutation is predicted to lock the motif in this position. In contrast, phosphorylation of Ser-1248 will drive profound structural transition of the sequence, critically affecting connection of the C terminus as well as exposing potential protein docking sites. Decreased kinase activity of a phosphomimetic S1248E mutant and enhanced kinase activity in mutants of its predicted target residue Lys-1081 support this auto-inhibitory model. Thus, the SFYYS motif controls the organization of the IGF-1R C terminus relative to the kinase domain. Its phosphorylation by GSK-3β restrains kinase activity and regulates receptor trafficking and signaling.
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