Inhibition of basal FGF receptor signaling by dimeric Grb2

Chi Chuan Lin; Fernando A. Melo; Ragini Ghosh; Kin M. Suen; Loren J. Stagg; John Kirkpatrick; Stefan T. Arold; Zamal Ahmed; John E. Ladbury

doi:10.1016/j.cell.2012.04.033

Inhibition of basal FGF receptor signaling by dimeric Grb2

Chi Chuan Lin, Fernando A. Melo, Ragini Ghosh, Kin M. Suen, Loren J. Stagg, John Kirkpatrick, Stefan T. Arold, Zamal Ahmed, John E. Ladbury^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

138 Scopus citations

Abstract

Receptor tyrosine kinase activity is known to occur in the absence of extracellular stimuli. Importantly, this "background" level of receptor phosphorylation is insufficient to effect a downstream response, suggesting that strict controls are present and prohibit full activation. Here a mechanism is described in which control of FGFR2 activation is provided by the adaptor protein Grb2. Dimeric Grb2 binds to the C termini of two FGFR2 molecules. This heterotetramer is capable of a low-level receptor transphosphorylation, but C-terminal phosphorylation and recruitment of signaling proteins are sterically hindered. Upon stimulation, FGFR2 phosphorylates tyrosine residues on Grb2, promoting dissociation from the receptor and allowing full activation of downstream signaling. These observations establish a role for Grb2 as an active regulator of RTK signaling.

Original language	English (US)
Pages (from-to)	1514-1524
Number of pages	11
Journal	Cell
Volume	149
Issue number	7
DOIs	https://doi.org/10.1016/j.cell.2012.04.033
State	Published - Jun 22 2012
Externally published	Yes

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

Access to Document

10.1016/j.cell.2012.04.033

Cite this

@article{3862b8eda6d94f4fbead5192010b40a5,

title = "Inhibition of basal FGF receptor signaling by dimeric Grb2",

abstract = "Receptor tyrosine kinase activity is known to occur in the absence of extracellular stimuli. Importantly, this {"}background{"} level of receptor phosphorylation is insufficient to effect a downstream response, suggesting that strict controls are present and prohibit full activation. Here a mechanism is described in which control of FGFR2 activation is provided by the adaptor protein Grb2. Dimeric Grb2 binds to the C termini of two FGFR2 molecules. This heterotetramer is capable of a low-level receptor transphosphorylation, but C-terminal phosphorylation and recruitment of signaling proteins are sterically hindered. Upon stimulation, FGFR2 phosphorylates tyrosine residues on Grb2, promoting dissociation from the receptor and allowing full activation of downstream signaling. These observations establish a role for Grb2 as an active regulator of RTK signaling.",

author = "Lin, {Chi Chuan} and Melo, {Fernando A.} and Ragini Ghosh and Suen, {Kin M.} and Stagg, {Loren J.} and John Kirkpatrick and Arold, {Stefan T.} and Zamal Ahmed and Ladbury, {John E.}",

note = "Funding Information: This work was funded by the G. Harold and Leila Y. Mathers Charitable Foundation. ",

year = "2012",

month = jun,

day = "22",

doi = "10.1016/j.cell.2012.04.033",

language = "English (US)",

volume = "149",

pages = "1514--1524",

journal = "Cell",

issn = "0092-8674",

publisher = "Elsevier B.V.",

number = "7",

}

TY - JOUR

T1 - Inhibition of basal FGF receptor signaling by dimeric Grb2

AU - Lin, Chi Chuan

AU - Melo, Fernando A.

AU - Ghosh, Ragini

AU - Suen, Kin M.

AU - Stagg, Loren J.

AU - Kirkpatrick, John

AU - Arold, Stefan T.

AU - Ahmed, Zamal

AU - Ladbury, John E.

N1 - Funding Information: This work was funded by the G. Harold and Leila Y. Mathers Charitable Foundation.

PY - 2012/6/22

Y1 - 2012/6/22

N2 - Receptor tyrosine kinase activity is known to occur in the absence of extracellular stimuli. Importantly, this "background" level of receptor phosphorylation is insufficient to effect a downstream response, suggesting that strict controls are present and prohibit full activation. Here a mechanism is described in which control of FGFR2 activation is provided by the adaptor protein Grb2. Dimeric Grb2 binds to the C termini of two FGFR2 molecules. This heterotetramer is capable of a low-level receptor transphosphorylation, but C-terminal phosphorylation and recruitment of signaling proteins are sterically hindered. Upon stimulation, FGFR2 phosphorylates tyrosine residues on Grb2, promoting dissociation from the receptor and allowing full activation of downstream signaling. These observations establish a role for Grb2 as an active regulator of RTK signaling.

AB - Receptor tyrosine kinase activity is known to occur in the absence of extracellular stimuli. Importantly, this "background" level of receptor phosphorylation is insufficient to effect a downstream response, suggesting that strict controls are present and prohibit full activation. Here a mechanism is described in which control of FGFR2 activation is provided by the adaptor protein Grb2. Dimeric Grb2 binds to the C termini of two FGFR2 molecules. This heterotetramer is capable of a low-level receptor transphosphorylation, but C-terminal phosphorylation and recruitment of signaling proteins are sterically hindered. Upon stimulation, FGFR2 phosphorylates tyrosine residues on Grb2, promoting dissociation from the receptor and allowing full activation of downstream signaling. These observations establish a role for Grb2 as an active regulator of RTK signaling.

UR - http://www.scopus.com/inward/record.url?scp=84862669198&partnerID=8YFLogxK

U2 - 10.1016/j.cell.2012.04.033

DO - 10.1016/j.cell.2012.04.033

M3 - Article

C2 - 22726438

AN - SCOPUS:84862669198

SN - 0092-8674

VL - 149

SP - 1514

EP - 1524

JO - Cell

JF - Cell

IS - 7

ER -

Inhibition of basal FGF receptor signaling by dimeric Grb2

Abstract

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this