FAK signaling is critical for ErbB-2/ErbB-3 receptor cooperation for oncogenic transformation and invasion.
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.
Benlimame
Naciba
N
Department of Medicine, Lady Davis Institute of the Sir Mortimer B. Davis Jewish General Hospital, McGill University, Montreal, Quebec H3T 1E2, Canada.
He
Qiang
Q
Jie
Su
S
Xiao
Dingzhang
D
Xu
Ying Jie
YJ
Loignon
Martin
M
Schlaepfer
David D
DD
Alaoui-Jamali
Moulay A
MA
D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D002633:Chemotaxis; D004789:Enzyme Activation; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000235:genetics / Q000502:physiology*; D006801:Humans; D020935:MAP Kinase Signaling System / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D016513:Mice, SCID; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D010766:Phosphorylation; D019000:Phosphotyrosine / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000502:physiology*; D020893:Receptor, ErbB-3 / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction; D019061:src-Family Kinases / Q000502:physiology
D051416:Focal Adhesion Protein-Tyrosine Kinases; D019000:Phosphotyrosine; D034741:RNA, Small Interfering; D018719:Erb-b2 Receptor Tyrosine Kinases; D020893:Receptor, ErbB-3; D019061:src-Family Kinases