Serine Phosphorylation of the Insulin-like Growth Factor I (IGF-1) Receptor C-terminal Tail Restrains Kinase Activity and Cell Growth

Kelly, G.; Buckley, Deirdre A.; Kiely, Patrick A.; Adams, David H.; O’Connor, Rosemary

doi:10.1074/jbc.m112.385757

Cited by 26 publications

(18 citation statements)

References 56 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…As previously described, IGF-1R is a heterotetramer containing two α-and two β-subunits. Binding of the ligand (IGFs) to the α-subunit triggers a conformational change that leads to the autophosphorylation of a triple tyrosine cluster Tyr1131/1135/1136 of the intracellular kinase domain in the β-subunit (3,23). Autophosphorylation strongly enhances the activity of the IGF-1R catalytic domain.…”

Section: Discussionmentioning

confidence: 99%

Celecoxib inhibits insulin-like growth factor 1 induced growth and invasion in non-small cell lung cancer

Liu

Bao

et al. 2013

Oncology Letters

View full text Add to dashboard Cite

Despite a large number of studies indicating that celecoxib plays an important role in the prevention and treatment of tumors, the detailed molecular mechanisms are not well understood. The aim of the present study was to investigate the effect of celecoxib on insulin-like growth factor 1 (IGF-1)-induced growth and invasion in non-small cell lung cancer (NSCLC). For these experiments, IGF-1-induced cell growth and invasion were analyzed in A549 cells in the presence and absence of celecoxib. The effects of celecoxib on the expression of phosphorylated type-1 IGF receptor (IGF-1R) and phosphorylated AKT (p-AKT) were examined using western blot analysis. The influence of celecoxib on IGF-binding protein-3 (IGFBP-3) expression was analyzed using ELISA. Celecoxib inhibited IGF-1-stimulated growth and invasion in a dose-dependent manner. Celecoxib also reduced the expression of IGF-1R, IGFBP-3 and phosphorylation of AKT. The results suggest that modulating the IGF axis may be a new mechanism for the anticancer effect of celecoxib on NSCLC.

show abstract

Section: Discussionmentioning

confidence: 99%

Celecoxib inhibits insulin-like growth factor 1 induced growth and invasion in non-small cell lung cancer

Liu

Bao

et al. 2013

Oncology Letters

View full text Add to dashboard Cite

show abstract

“…Equivalent mutations are observed in HER2 and HER4, suggesting that disrupting this inhibitory mechanism is a common strategy for cancer cells to activate members of the EGFR family. In addition to the EGFR family, we note more examples of C‐terminal tail interactions mediated by the αC‐β4 loop in MAPK family and IGF‐1R …”

Section: Disease Variants In the αC‐β4 Loopmentioning

confidence: 97%

Emerging roles of the αC‐β4 loop in protein kinase structure, function, evolution, and disease

2020

View full text Add to dashboard Cite

The faithful propagation of cellular signals in most organisms relies on the coordinated functions of a large family of protein kinases that share a conserved catalytic domain. The catalytic domain is a dynamic scaffold that undergoes large conformational changes upon activation. Most of these conformational changes, such as movement of the regulatory αC-helix from an "out"to "in" conformation, hinge on a conserved, but understudied, loop termed the αC-β4 loop, which mediates conserved interactions to tether flexible structural elements to the kinase core. We previously showed that the αC-β4 loop is a unique feature of eukaryotic protein kinases. Here, we review the emerging roles of this loop in kinase structure, function, regulation, and diseases. Through a kinome-wide analysis, we define the boundaries of the loop for the first time and show that sequence and structural variation in the loop correlate with conformational and regulatory variation. Many recurrent disease mutations map to the αC-β4 loop and contribute to drug resistance and abnormal kinase activation by relieving key auto-inhibitory interactions associated with αC-helix and interlobe movement. The αC-β4 loop is a hotspot for post-translational modifications, protein-protein interaction, and Hsp90 mediated folding. Our kinome-wide analysis provides insights for hypothesis-driven characterization of understudied kinases and the development of allosteric protein kinase inhibitors.

show abstract

“…Other receptors reported to be phosphorylated by GSK3 include the androgen receptor, which reduces its activation of transcription (Salas et al, 2004; Wang et al, 2004), the prolactin receptor, which targets it for proteasomal degradation (Plotnikov et al, 2008), the progesterone receptor, which regulates its stability (Wang et al, 2013b), LRP6, which promotes the recruitment of Axin to LRP6 (Zeng et al, 2005), and the IGF-1 receptor, which regulates its signaling and trafficking (Nemoto et al, 2010; Kelly et al, 2012). …”

Section: Gsk3 Interactions With Receptors and Receptor-coupled Sigmentioning

confidence: 99%

Glycogen synthase kinase-3 (GSK3): Regulation, actions, and diseases

Beurel

Grieco

Jope

2015

Pharmacology & Therapeutics

1,390

1,178

View full text Add to dashboard Cite

Glycogen synthase kinase-3 (GSK3) may be the busiest kinase in most cells, with over 100 known substrates to deal with. How does GSK3 maintain control to selectively phosphorylate each substrate, and why was it evolutionarily favorable for GSK3 to assume such a large responsibility? GSK3 must be particularly adaptable for incorporating new substrates into its repertoire, and we discuss the distinct properties of GSK3 that may contribute to its capacity to fulfill its roles in multiple signaling pathways. The mechanisms regulating GSK3 (predominantly post-translational modifications, substrate priming, cellular trafficking, protein complexes) have been reviewed previously, so here we focus on newly identified complexities in these mechanisms, how each of these regulatory mechanism contributes to the ability of GSK3 to select which substrates to phosphorylate, and how these mechanisms may have contributed to its adaptability as new substrates evolved. The current understanding of the mechanisms regulating GSK3 is reviewed, as are emerging topics in the actions of GSK3, particularly its interactions with receptors and receptor-coupled signal transduction events, and differential actions and regulation of the two GSK3 isoforms, GSK3α and GSK3β. Another remarkable characteristic of GSK3 is its involvement in many prevalent disorders, including psychiatric and neurological diseases, inflammatory diseases, cancer, and others. We address the feasibility of targeting GSK3 therapeutically, and provide an update of its involvement in the etiology and treatment of several disorders.

show abstract

Serine Phosphorylation of the Insulin-like Growth Factor I (IGF-1) Receptor C-terminal Tail Restrains Kinase Activity and Cell Growth

Cited by 26 publications

References 56 publications

Celecoxib inhibits insulin-like growth factor 1 induced growth and invasion in non-small cell lung cancer

Celecoxib inhibits insulin-like growth factor 1 induced growth and invasion in non-small cell lung cancer

Emerging roles of the αC‐β4 loop in protein kinase structure, function, evolution, and disease

Glycogen synthase kinase-3 (GSK3): Regulation, actions, and diseases

Contact Info

Product

Resources

About