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Cited by 158Fibroblast Growth Factor ResearchProtein Kinase Regulation and GTPase SignalingProtein Tyrosine Phosphatases

The Selectivity of Receptor Tyrosine Kinase Signaling Is Controlled by a Secondary SH2 Domain Binding Site

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Bae, Jae Hyun, Lew, Erin Denise, Yuzawa, Satoru, Tomé, Francisco, Lax, Irit, Schlessinger, Joseph·2009·Cell
DOI 10.1016/j.cell.2009.05.028PMC PMC4764080
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Abstract

SH2 domain-mediated interactions represent a crucial step in transmembrane signaling by receptor tyrosine kinases. SH2 domains recognize phosphotyrosine (pY) in the context of particular sequence motifs in receptor phosphorylation sites. However, the modest binding affinity of SH2 domains to pY containing peptides may not account for and likely represents an oversimplified mechanism for regulation of selectivity of signaling pathways in living cells. Here we describe the crystal structure of the activated tyrosine kinase domain of FGFR1 in complex with a phospholipase Cgamma fragment. The structural and biochemical data and experiments with cultured cells show that the selectivity of phospholipase Cgamma binding and signaling via activated FGFR1 are determined by interactions between a secondary binding site on an SH2 domain and a region in FGFR1 kinase domain in a phosphorylation independent manner. These experiments reveal a mechanism for how SH2 domain selectivity is regulated in vivo to mediate a specific cellular process.

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Cited by

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Authors
Bae, J. H., Lew, E. D., Yuzawa, S., Tomé, F., Lax, I., & Schlessinger, J.
Affiliations
Yale University (US)
Corresponding author
Schlessinger, Joseph
ORCID
Venue
Cell
Publisher
Elsevier BV
Published
2009-08
Volume
138
Issue
3
Pages
514-524
ISSN
0092-8674 (ISSN-L)
DOI
10.1016/j.cell.2009.05.028
PMC
PMC4764080
OpenAlex
W2160284078
Cited by
158
References
0
Citations by year
2026: 3 · 2025: 9 · 2024: 4 · 2023: 8 · 2022: 6 · 2021: 16 · 2020: 9 · 2019: 10 · 2018: 5 · 2017: 7 · 2016: 7 · 2015: 13 · 2014: 8 · 2013: 11 · 2012: 15
FWCI
5.64
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institutes of Health
  • National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01AR051448, P50AR054086, R01AR051886)
  • Brookhaven National Laboratory
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fibroblast Growth Factor Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
Keywords
receptor tyrosine kinase signaling, SH2 domain, FGFR1, phospholipase C-gamma, secondary binding site, phosphotyrosine recognition, kinase domain, protein-protein interaction, crystal structure
MeSH terms
Amino Acid Sequence, Animals, Humans, Models, Molecular, Molecular Sequence Data, Signal Transduction, Sequence Alignment, src Homology Domains, Phosphotyrosine, Mice, Receptor, Fibroblast Growth Factor, Type 1

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