Molecular basis for receptor tyrosine kinase A-loop tyrosine transphosphorylation

Chen, Lingfeng; Marsiglia, William M.; Chen, Huaibin; Katigbak, Joseph; Erdjument‐Bromage, Hediye; Kemble, David J.; Fu, Lili; Ma, Jinghong; Sun, Gongqin; Zhang, Yingkai; Liang, Guang; Neubert, Thomas A.; Li, Xiaokun; Traaseth, Nathaniel J.; Mohammadi, Moosa

doi:10.1038/s41589-019-0455-7

Cited by 37 publications

(48 citation statements)

References 42 publications

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“…Recent cryo-EM analyses show insulin induces a hinge motion in this linker to swing the fibronectin domains inward, bringing together the intracellular domains of each protomer (63,71,72). This proximity permits asymmetric kinase transphosphorylation, a non-reciprocal process whereby the kinase domain of one protomer acts as enzyme to phosphorylate the opposing (substrate) activation loop (A-loop) (45,64,73). Phosphorylation of the substrate A-loop releases the catalytic potential of its corresponding kinase and the dimer has full function derived from activation of this one kinase domain.…”

Section: Inr E19 : Extracellular Fibronectin Domainmentioning

confidence: 99%

“…Pro1466Ser. We can gain insights on this segment from human the fibroblast growth factor receptor FGFR3 where the homolgous C-terminal region stabilizes the asymmetric dimer interface required for transphosphorylation (64). C. elegans Pro1466 corresponds to P694 of FGFR3, and substitution to serine will disrupt a stabilizing hydrogen bond in this interface.…”

Section: Inr 211(hr) : Kinase Domain C-terminal Lobementioning

confidence: 99%

“…Lines with EMS-induced point mutations at InR generated on a 'rutipa' genetic background, balanced by TM3,Sb (provided in 1999 by M. Frasch, The Mount Sinai School of Medicine, 'Frasch series') (58,59). We tested the ability of 17 mutant lines from this collection to produce viable adults when complemented to the EMS-induced mutant allele InR E19 provided by J. Jack (University of Connecticut School of Medicine, in 1999) (64). We previously reported was used in each block of demographic analysis to provide a common strain to normalize survival data across test periods.…”

Section: Ems Mutant Inr Allelesmentioning

confidence: 99%

“…We validate and extend these results by independently generating the putative substitutions of the InR EMS alleles through homologous recombination gene replacement and evaluate lifespan, growth, development rate and fecundity. Finally, recent advances provide remarkable insights into the structure of activated human insulin receptors (63,64). We combine these data with our genetic analysis to generate new ways to understand how the insulin-like receptor modulates aging.…”

Section: Introductionmentioning

confidence: 99%

“…3) The genetic effects of InR alleles may be understood through the model of tyrosine kinase receptor activation by asymmetric transphosphorylation (45,64). In wildtype homodimeric receptors the direction of asymmetry is random.…”

Section: Introductionmentioning

confidence: 99%

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MappingDrosophilainsulin receptor structure to the regulation of aging through analysis of amino acid substitutions

Yamamoto

Palmer

Koski

et al. 2020

Preprint

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ABSTRACTGenetic manipulations of the Drosophila insulin/IGF signaling system slow aging, but it remains unknown how the insulin/IGF receptor acts to modulate lifespan or differentiate this control from that of growth, reproduction and metabolism. With homologous recombination we produced an allelic series of single amino acid substitutions in the fly insulin receptor (InR). Based on emerging biochemical and structural data, we map amino acid substitutions to receptor function to longevity and fecundity. We propose InR mutants generate bias in the process of asymmetric transphosphorylation when the receptor is activated. This induces specific kinase subdomains that modulate lifespan by additive processes, one involving survival costs of reproduction and the other involving reproduction-independent systems of longevity assurance. We identify a mutant in the kinase insert domain that robustly extends lifespan without affecting growth or reproduction, suggesting this element controls aging through unique mechanisms of longevity assurance.

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Section: Inr E19 : Extracellular Fibronectin Domainmentioning

confidence: 99%

Section: Inr 211(hr) : Kinase Domain C-terminal Lobementioning

confidence: 99%

Section: Ems Mutant Inr Allelesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

MappingDrosophilainsulin receptor structure to the regulation of aging through analysis of amino acid substitutions

Yamamoto

Palmer

Koski

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

New developments in the biology of fibroblast growth factors

Ornitz

Itoh

2022

WIREs Mechanisms of Disease

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The fibroblast growth factor (FGF) family is composed of 18 secreted signaling proteins consisting of canonical FGFs and endocrine FGFs that activate four receptor tyrosine kinases (FGFRs 1-4) and four intracellular proteins (intracellular FGFs or iFGFs) that primarily function to regulate the activity of voltagegated sodium channels and other molecules. The canonical FGFs, endocrine FGFs, and iFGFs have been reviewed extensively by us and others. In this review, we briefly summarize past reviews and then focus on new developments in the FGF field since our last review in 2015. Some of the highlights in the past 6 years include the use of optogenetic tools, viral vectors, and inducible transgenes to experimentally modulate FGF signaling, the clinical use of small molecule FGFR inhibitors, an expanded understanding of endocrine FGF signaling, functions for FGF signaling in stem cell pluripotency and differentiation, roles for FGF signaling in tissue homeostasis and regeneration, a continuing elaboration of mechanisms of FGF signaling in development, and an expanding appreciation of roles for FGF signaling in neuropsychiatric diseases.

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Elucidating the potential effects of point mutations on FGFR3 inhibitor resistance via combined molecular dynamics simulation and community network analysis

Liu

Ding

Liu

et al. 2023

J Comput Aided Mol Des

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Molecular basis for receptor tyrosine kinase A-loop tyrosine transphosphorylation

Cited by 37 publications

References 42 publications

MappingDrosophilainsulin receptor structure to the regulation of aging through analysis of amino acid substitutions

MappingDrosophilainsulin receptor structure to the regulation of aging through analysis of amino acid substitutions

New developments in the biology of fibroblast growth factors

Elucidating the potential effects of point mutations on FGFR3 inhibitor resistance via combined molecular dynamics simulation and community network analysis

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