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

Overview

Journal Cell

Publisher Cell Press

Specialty Cell Biology

Date 2009 Aug 12

PMID 19665973

Citations 81

Authors

Jae Hyun Bae

Erin Denise Lew

Satoru Yuzawa

Francisco Tome

Irit Lax

Joseph Schlessinger

Affiliations

Soon will be listed here.

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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References

Piccione E, Case R, Domchek S, Hu P, Chaudhuri M, Backer J . Phosphatidylinositol 3-kinase p85 SH2 domain specificity defined by direct phosphopeptide/SH2 domain binding. Biochemistry. 1993; 32(13):3197-202. DOI: 10.1021/bi00064a001. View

Chattopadhyay A, Vecchi M, Ji Q, Mernaugh R, Carpenter G . The role of individual SH2 domains in mediating association of phospholipase C-gamma1 with the activated EGF receptor. J Biol Chem. 1999; 274(37):26091-7. DOI: 10.1074/jbc.274.37.26091. View

Groesch T, Zhou F, Mattila S, Geahlen R, Post C . Structural basis for the requirement of two phosphotyrosine residues in signaling mediated by Syk tyrosine kinase. J Mol Biol. 2006; 356(5):1222-36. DOI: 10.1016/j.jmb.2005.11.095. View

Pawson T, Nash P . Assembly of cell regulatory systems through protein interaction domains. Science. 2003; 300(5618):445-52. DOI: 10.1126/science.1083653. View

Schlessinger J, Lemmon M . SH2 and PTB domains in tyrosine kinase signaling. Sci STKE. 2003; 2003(191):RE12. DOI: 10.1126/stke.2003.191.re12. View

Favelyukis S, Till J, Hubbard S, Miller W . Structure and autoregulation of the insulin-like growth factor 1 receptor kinase. Nat Struct Biol. 2001; 8(12):1058-63. DOI: 10.1038/nsb721. View

Minor W, Tomchick D, Otwinowski Z . Strategies for macromolecular synchrotron crystallography. Structure. 2000; 8(5):R105-10. DOI: 10.1016/s0969-2126(00)00139-8. View

Furdui C, Lew E, Schlessinger J, Anderson K . Autophosphorylation of FGFR1 kinase is mediated by a sequential and precisely ordered reaction. Mol Cell. 2006; 21(5):711-7. DOI: 10.1016/j.molcel.2006.01.022. View

Poulin B, Sekiya F, Rhee S . Intramolecular interaction between phosphorylated tyrosine-783 and the C-terminal Src homology 2 domain activates phospholipase C-gamma1. Proc Natl Acad Sci U S A. 2005; 102(12):4276-81. PMC: 555506. DOI: 10.1073/pnas.0409590102. View

10.

Waksman G, Shoelson S, Pant N, Cowburn D, Kuriyan J . Binding of a high affinity phosphotyrosyl peptide to the Src SH2 domain: crystal structures of the complexed and peptide-free forms. Cell. 1993; 72(5):779-90. DOI: 10.1016/0092-8674(93)90405-f. View

11.

Ladbury J, Arold S . Searching for specificity in SH domains. Chem Biol. 2000; 7(1):R3-8. DOI: 10.1016/s1074-5521(00)00067-3. View

12.

Larose L, Gish G, Pawson T . Construction of an SH2 domain-binding site with mixed specificity. J Biol Chem. 1995; 270(8):3858-62. DOI: 10.1074/jbc.270.8.3858. View

13.

Donaldson L, Gish G, Pawson T, Kay L, Forman-Kay J . Structure of a regulatory complex involving the Abl SH3 domain, the Crk SH2 domain, and a Crk-derived phosphopeptide. Proc Natl Acad Sci U S A. 2002; 99(22):14053-8. PMC: 137835. DOI: 10.1073/pnas.212518799. View

14.

McCoy A, Grosse-Kunstleve R, Adams P, Winn M, Storoni L, Read R . Phaser crystallographic software. J Appl Crystallogr. 2009; 40(Pt 4):658-674. PMC: 2483472. DOI: 10.1107/S0021889807021206. View

15.

Poirot O, OToole E, Notredame C . Tcoffee@igs: A web server for computing, evaluating and combining multiple sequence alignments. Nucleic Acids Res. 2003; 31(13):3503-6. PMC: 168929. DOI: 10.1093/nar/gkg522. View

16.

Kleywegt G . Crystallographic refinement of ligand complexes. Acta Crystallogr D Biol Crystallogr. 2006; 63(Pt 1):94-100. PMC: 2483469. DOI: 10.1107/S0907444906022657. View

17.

Poulin B, Sekiya F, Rhee S . Differential roles of the Src homology 2 domains of phospholipase C-gamma1 (PLC-gamma1) in platelet-derived growth factor-induced activation of PLC-gamma1 in intact cells. J Biol Chem. 2000; 275(9):6411-6. DOI: 10.1074/jbc.275.9.6411. View

18.

Lax I, Wong A, Lamothe B, Lee A, Frost A, Hawes J . The docking protein FRS2alpha controls a MAP kinase-mediated negative feedback mechanism for signaling by FGF receptors. Mol Cell. 2002; 10(4):709-19. DOI: 10.1016/s1097-2765(02)00689-5. View

19.

Jones R, Gordus A, Krall J, MacBeath G . A quantitative protein interaction network for the ErbB receptors using protein microarrays. Nature. 2005; 439(7073):168-74. DOI: 10.1038/nature04177. View

20.

Brunger A, Adams P, Clore G, DeLano W, Gros P, Grosse-Kunstleve R . Crystallography & NMR system: A new software suite for macromolecular structure determination. Acta Crystallogr D Biol Crystallogr. 1998; 54(Pt 5):905-21. DOI: 10.1107/s0907444998003254. View