Integration of the beta-catenin-dependent Wnt pathway with integrin signaling through the adaptor molecule Grb2.
BACKGROUND
THE COMPLEXITY OF WNT SIGNALING LIKELY STEMS FROM TWO SOURCES: multiple pathways emanating from frizzled receptors in response to wnt binding, and modulation of those pathways and target gene responsiveness by context-dependent signals downstream of growth factor and matrix receptors. Both rac1 and c-jun have recently been implicated in wnt signaling, however their upstream activators have not been identified.


RESULTS
Here we identify the adapter protein Grb2, which is itself an integrator of multiple signaling pathways, as a modifier of beta-catenin-dependent wnt signaling. Grb2 synergizes with wnt3A, constitutively active (CA) LRP6, Dvl2 or CA-beta-catenin to drive a LEF/TCF-responsive reporter, and dominant negative (DN) Grb2 or siRNA to Grb2 block wnt3A-mediated reporter activity. MMP9 is a target of beta-catenin-dependent wnt signaling, and an MMP9 promoter reporter is also responsive to signals downstream of Grb2. Both a jnk inhibitor and DN-c-jun block transcriptional activation downstream of Dvl2 and Grb2, as does DN-rac1. Integrin ligation by collagen also synergizes with wnt signaling as does overexpression of Focal Adhesion Kinase (FAK), and this is blocked by DN-Grb2.


CONCLUSIONS
These data suggest that integrin ligation and FAK activation synergize with wnt signaling through a Grb2-rac-jnk-c-jun pathway, providing a context-dependent mechanism for modulation of wnt signaling.
Crampton
Steve P
SP
Department of Molecular Biology and Biochemistry, UCI Institute for Immunology, University of California Irvine, Irvine, California, USA.
Wu
Beibei
B
Park
Edward J
EJ
Kim
Jai-Hyun
JH
Solomon
Candice
C
Waterman
Marian L
ML
Hughes
Christopher C W
CC
D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000378:metabolism; D051380:GRB2 Adaptor Protein / Q000378:metabolism*; D005786:Gene Expression Regulation; D005799:Genes, Dominant; D006801:Humans; D016023:Integrins / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction; D051153:Wnt Proteins / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism*; D020830:rac1 GTP-Binding Protein / Q000378:metabolism
D051380:GRB2 Adaptor Protein; C495948:GRB2 protein, human; D016023:Integrins; D016755:Proto-Oncogene Proteins c-jun; C107953:RAC1 protein, human; D034741:RNA, Small Interfering; D051153:Wnt Proteins; D051176:beta Catenin; D051416:Focal Adhesion Protein-Tyrosine Kinases; D020780:Matrix Metalloproteinase 9; D020830:rac1 GTP-Binding Protein