The SH2/SH3 adaptor Grb4 transduces B-ephrin reverse signals

C. A. Cowan, M. Henkemeyer

Research output: Contribution to journalArticle

268 Citations (Scopus)

Abstract

Bidirectional signals mediated by membrane-anchored ephrins and Eph receptor tyrosine kinases have important functions in cell-cell recognition events, including those that occur during axon pathfinding1,2 and hindbrain segmentation3,4. The reverse signal that is transduced into B-ephrin-expressing cells is thought to involve tyrosine phosphorylation of the signal's short, conserved carboxy-terminal cytoplasmic domain5,6. The Src-homology-2 (SH2) domain proteins that associate with activated tyrosinephosphorylated B-subclass ephrins have not been identified, nor has a defined cellular response to reverse signals been described. Here we show that the SH2/SH3 domain adaptor protein Grb4 binds to the cytoplasmic domain of B ephrins in a phosphotyrosine-dependent manner. In response to B-ephrin reverse signalling, cells increase FAK catalytic activity, redistribute paxillin, lose focal adhesions, round up, and disassemble F-actin-containing stress fibres. These cellular responses can be blocked in a dominant-negative fashion by expression of the isolated Grb4 SH2 domain. The Grb4 SH3 domains bind a unique set of other proteins that are implicated in cytoskeletal regulation, including the Cb1-associated protein (CAP/ponsin), the Ab1-interacting protein-1 (Abi-1), dynamin, PAK1, hnRNPK and axin. These data provide a biochemical pathway whereby cytoskeletal regulators are recruited to Eph-ephrin bidirectional signalling complexes.

Original languageEnglish (US)
Pages (from-to)174-179
Number of pages6
JournalNature
Volume413
Issue number6852
DOIs
StatePublished - Sep 13 2001

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Ephrins
src Homology Domains
Proteins
Dynamin I
Eph Family Receptors
Paxillin
Stress Fibers
Rhombencephalon
Phosphotyrosine
Focal Adhesions
Axons
Tyrosine
Actins
Phosphorylation
Membranes

ASJC Scopus subject areas

  • General

Cite this

The SH2/SH3 adaptor Grb4 transduces B-ephrin reverse signals. / Cowan, C. A.; Henkemeyer, M.

In: Nature, Vol. 413, No. 6852, 13.09.2001, p. 174-179.

Research output: Contribution to journalArticle

Cowan, C. A. ; Henkemeyer, M. / The SH2/SH3 adaptor Grb4 transduces B-ephrin reverse signals. In: Nature. 2001 ; Vol. 413, No. 6852. pp. 174-179.
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