Integrin-mediated signal transduction linked to Ras pathway by GRB2 binding to focal adhesion kinase
Abstract
The cytoplasmic focal adhesion protein-tyrosine kinase (FAK) localizes with surface integrin receptors at sites where cells attach to the extracellular matrix. Increased FAK tyrosine phosphorylation occurs upon integrin engagement with fibronectin. Here we show that adhesion of murine NIH3T3 fibroblasts to fibronectin promotes SH2-domain-mediated association of the GRB2 adaptor protein and the c-Src protein-tyrosine kinase (PTK) with FAK in vivo, and also results in activation of mitogen-activated protein kinase (MAPK). In v-Src-transformed NIH3T3, the association of v-Src, GRB2 and Sos with FAK is independent of cell adhesion to fibronectin. The GRB2 SH2 domain binds directly to tyrosine-phosphorylated FAK. Mutation of tyrosine residue 925 of FAK (YENV motif) to phenylalanine blocks GRB2 SH2-domain binding to FAK in vitro. Our results show that fibronectin binding to integrins on NIH3T3 fibroblasts promotes c-Src and FAK association and formation of an integrin-activated signalling complex. Phosphorylation of FAK at Tyr 925 upon fibronectin stimulation creates an SH2-binding site for GRB2 which may link integrin engagement to the activation of the Ras/MAPK signal transduction pathway.
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FAK is a downstream signaling component of KRAS.
“First, FAK is a downstream signaling component of KRAS, emphasizing its directly linked function in supporting the KRAS activity.[ 14, 42 ]”
From Focal Adhesion Kinase (FAK) Inhibition Synergizes with KRAS G12C Inhibitors in Treating Cancer through the Regulation of the FAK–YAP Signaling (2021) · cites this paper as [42]
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- Authors
- Schlaepfer, D. D., Hanks, S. K., Hunter, T., & Geer, P. V. D.
- Affiliations
- Salk Institute for Biological Studies (US)
- Vanderbilt University (US)
- Mount Sinai Hospital (CA)
- Venue
- Nature
- Published
- 1994-12
- Volume
- 372
- Issue
- 6508
- Pages
- 786-791
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W2054779757
- Cited by
- 1,595
- References
- 22
- Citations by year
- 2026: 13 · 2025: 15 · 2024: 23 · 2023: 18 · 2022: 25 · 2021: 23 · 2020: 29 · 2019: 24 · 2018: 12 · 2017: 30 · 2016: 28 · 2015: 18 · 2014: 35 · 2013: 30 · 2012: 35
- FWCI
- 40.33
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Immunology and Allergy › Cell Adhesion Molecules Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular Mechanics and Interactions
- Keywords
- focal adhesion kinase, Grb2, integrin signaling, RAS/MAPK pathway, Src kinase, fibronectin, cell adhesion, tyrosine phosphorylation, SH2 domain binding, SO, NIH3T3 cells, extracellular matrix, signal transduction
- MeSH terms
- CSK Tyrosine-Protein Kinase, Amino Acid Sequence, Animals, Cell Adhesion, Chickens, Enzyme Activation, Fibronectins, Humans, Phosphorylation, Precipitin Tests, Protein Kinases, Protein-Tyrosine Kinases, Proteins, Recombinant Fusion Proteins, Tyrosine, Signal Transduction, Oncogene Protein pp60(v-src), Cell Adhesion Molecules, Integrins, 3T3 Cells, src-Family Kinases, Adaptor Proteins, Signal Transducing, Mice, GRB2 Adaptor Protein, Focal Adhesion Protein-Tyrosine Kinases, Focal Adhesion Kinase 1, ErbB Receptors
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