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Published 7 November 2005. doi:10.1083/jcb.200504124
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 171, Number 3, 505-516
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Article

 FAK signaling is critical for ErbB-2/ErbB-3 receptor cooperation for oncogenic transformation and invasion

Naciba Benlimame1,2, Qiang He1,2, Su Jie1,2, Dingzhang Xiao1,2, Ying Jie Xu1,2, Martin Loignon1,2, David D. Schlaepfer3, and Moulay A. Alaoui-Jamali1,2

1 Department of Medicine, Lady Davis Institute of the Sir Mortimer B. Davis Jewish General Hospital, McGill University, Montreal, Quebec H3T 1E2, Canada
2 Department of Oncology, Lady Davis Institute of the Sir Mortimer B. Davis Jewish General Hospital, McGill University, Montreal, Quebec H3T 1E2, Canada
3 The Scripps Research Institute, La Jolla, CA 92037

Correspondence to Moulay A Alaoui-Jamali: moulay.alaoui-jamali{at}mcgill.ca

The overexpression of members of the ErbB tyrosine kinase receptor family has been associated with cancer progression. We demonstrate that focal adhesion kinase (FAK) is essential for oncogenic transformation and cell invasion that is induced by ErbB-2 and -3 receptor signaling. ErbB-2/3 overexpression in FAK-deficient cells fails to promote cell transformation and rescue chemotaxis deficiency. Restoration of FAK rescues both oncogenic transformation and invasion that is induced by ErbB-2/3 in vitro and in vivo. In contrast, the inhibition of FAK in FAK-proficient invasive cancer cells prevented cell invasion and metastasis formation. The activation of ErbB-2/3 regulates FAK phosphorylation at Tyr-397, -861, and -925. ErbB-induced oncogenic transformation correlates with the ability of FAK to restore ErbB-2/3–induced mitogen-activated protein kinase (MAPK) activation; the inhibition of MAPK prevented oncogenic transformation. In contrast, the inhibition of Src but not MAPK prevented ErbB–FAK-induced chemotaxis. In migratory cells, activated ErbB-2/3 receptors colocalize with activated FAK at cell protrusions. This colocalization requires intact FAK. In summary, distinct FAK signaling has an essential function in ErbB-induced oncogenesis and invasiveness.

N. Benlimame and Q. He contributed equally to this paper.

Q. He's present address is Department of Hepatobiliary Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510089, China.

Abbreviations used in this paper: CT, COOH terminus; ERK, extracellular regulated kinase; HRG, heregulin; NT, NH2 terminus; siRNA, short inhibitory RNA.


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