Small-molecule inhibition and activation-loop trans-phosphorylation of the IGF1 receptor

Wu, Jiangxue; Li, Wanqing; Craddock, Barbara P.; Foreman, Kenneth W.; Mulvihill, Mark J.; Ji, Qunsheng; Miller, W. Todd; Hubbard, Stevan R.

doi:10.1038/emboj.2008.116

Cited by 76 publications

(82 citation statements)

References 47 publications

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“…It was shown many years ago that Y1162 was the first of the three tyrosines in the IRK activation loop to undergo autophosphorylation, followed by Y1158 and Y1163 (Wei et al 1995). Several years ago, a crystal structure of the IGF1R kinase domain (IGF1RK) was determined in which the tyrosine equivalent to Y1162, Y1135, was bound in the active site of a symmetry-related kinase domain (in trans) (Wu et al 2008a). This configuration was made possible through the tight binding of an ATPcompetitive small-molecule inhibitor, which forced the activation loop out of its pseudosubstrate configuration.…”

Section: Sr Hubbardmentioning

confidence: 99%

The Insulin Receptor: Both a Prototypical and Atypical Receptor Tyrosine Kinase

Hubbard

2013

Cold Spring Harbor Perspectives in Biology

130

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Unlike prototypical receptor tyrosine kinases (RTKs), which are single-chain polypeptides, the insulin receptor (InsR) is a preformed, covalently linked tetramer with two extracellular a subunits and two membrane-spanning, tyrosine kinase-containing b subunits. A single molecule of insulin binds asymmetrically to the ectodomain, triggering a conformational change that is transmitted to the cytoplasmic kinase domains, which facilitates their trans-phosphorylation. As in prototypical RTKs, tyrosine phosphorylation in the juxtamembrane region of InsR creates recruitment sites for downstream signaling proteins (IRS [InsR substrate] proteins, Shc) containing a phosphotyrosine-binding (PTB) domain, and tyrosine phosphorylation in the kinase activation loop stimulates InsR's catalytic activity. For InsR, phosphorylation of the activation loop, which contains three tyrosine residues, also creates docking sites for adaptor proteins (Grb10/14, SH2B2) that possess specialized Src homology-2 (SH2) domains, which are dimeric and engage two phosphotyrosines in the activation loop.

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Section: Sr Hubbardmentioning

confidence: 99%

The Insulin Receptor: Both a Prototypical and Atypical Receptor Tyrosine Kinase

Hubbard

2013

Cold Spring Harbor Perspectives in Biology

130

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“…IGF-IR is a transmembrane protein consisting of two extracellular α-subunits, which contain the cysteine-rich ligand binding site, and two transmembrane β-subunits that have a cluster of three tyrosine residues, which undergo phosphorylation and activation upon IGF-I binding (2,110,114). A structural rearrangement in the transmembrane β subunits of the receptor is caused by binding of IGF-I to IGF-IR, resulting in transautophosphorylation of the cytoplasmic tyrosine kinase domain of the receptor, as one kinase domain phosphorylates the other, and thus destabilizing the autoinhibitory conformation within the kinase domain (115,116). This conformational change permits unrestricted access to the binding sites for protein substrates (117), thus recruiting specific cytoplasmic molecules, such as insulin receptor substrate (IRS) proteins, and activating specific intracellular pathways including Ras/mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinases 1 and 2 (ERK1/2) and phosphatidylinositol 3-kinase (PI3K)/ Akt (118).…”

Section: Igf-i Receptors and Binding Proteins Igf-i Actions Are Mediamentioning

confidence: 99%

The Complexity of the IGF1 Gene Splicing, Posttranslational Modification and Bioactivity

Philippou

Maridaki

Pneumaticos

et al. 2014

Mol Med

100

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The insulinlike growth factor-I (IGF-I) is an important factor which regulates a variety of cellular responses in multiple biological systems. The IGF1 gene comprises a highly conserved sequence and contains six exons, which give rise to heterogeneous mRNA transcripts by a combination of multiple transcription initiation sites and alternative splicing. These multiple transcripts code for different precursor IGF-I polypeptides, namely the IGF-IEa, IGF-IEb and IGF-IEc isoforms in humans, which also undergo posttranslational modifications, such as proteolytic processing and glycosylation. IGF-I actions are mediated through its binding to several cell-membrane receptors and the IGF-I domain responsible for the receptor binding is the bioactive mature IGF-I peptide, which is derived after the posttranslational cleavage of the pro-IGF-I isoforms and the removal of their carboxy-terminal E-peptides (that is, the Ea, Eb and Ec). Interestingly, differential biological activities have been reported for the different IGF-I isoforms, or for their E-peptides, implying that IGF-I peptides other than the IGF-I ligand also possess bioactivity and, thus, both common and unique or complementary pathways exist for the IGF-I isoforms to promote biological effects. The multiple peptides derived from IGF-I and the differential expression of its various transcripts in different conditions and pathologies appear to be compatible with the distinct cellular responses observed to the different IGF-I peptides and with the concept of a complex and possibly isoform-specific IGF-I bioactivity. This concept is discussed in the present review, in the context of the broad range of modifications that this growth factor undergoes which might regulate its mechanism(s) of action.

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“…Mutation of Lys-1138 to Arg would not necessarily prevent salt bridge formation but could change its conformation somewhat. However, we cannot exclude the possibility that other kinases may mediate IGF-IR phosphorylation at other sites, although current models posit that IGF-IR is only transphosphorylated by itself (14,44).…”

Section: Discussionmentioning

confidence: 99%

Polyubiquitination of Insulin-like Growth Factor I Receptor (IGF-IR) Activation Loop Promotes Antibody-induced Receptor Internalization and Down-regulation

Mao¹,

Shang²,

Pham³

et al. 2011

Journal of Biological Chemistry

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Background: Insulin-like growth factor I receptor (IGF-IR) can be down-regulated by antibodies and ligand, but its ubiquitination sites remain unknown. Results: The IGF-IR ubiquitination sites were mapped to its activation loop adjacent to the phosphorylation sites. Conclusion: IGF-IR requires phosphorylation of its activation loop followed by Lys-48-and Lys-29-linked ubiquitination for down-regulation. Significance: This is the first mapping of IGF-IR ubiquitination sites.

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Small-molecule inhibition and activation-loop trans-phosphorylation of the IGF1 receptor

Cited by 76 publications

References 47 publications

The Insulin Receptor: Both a Prototypical and Atypical Receptor Tyrosine Kinase

The Insulin Receptor: Both a Prototypical and Atypical Receptor Tyrosine Kinase

The Complexity of the IGF1 Gene Splicing, Posttranslational Modification and Bioactivity

Polyubiquitination of Insulin-like Growth Factor I Receptor (IGF-IR) Activation Loop Promotes Antibody-induced Receptor Internalization and Down-regulation

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