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

Abstract

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.

Intrinsic focal adhesion kinase activity controls orthotopic breast carcinoma metastasis via the regulation of urokinase plasminogen activator expression in a syngeneic tumor model

“…This conclusion is supported by the fact that v-Src-stimulated cell invasion is linked to the formation of a FAK-Src-p130Cas-Dock180 signaling complex, elevated Rac and JNK activation and increased MMP expression and activity (Hsia et al, 2003). Further, inhibition of Src and MAPK activation blocks an ErbB2/3 to FAK signaling linkage, promoting cell invasion (Benlimame et al, 2005). As we found that uPA expression in 4T1 FAK shRNA cells was rescued by constitutively active MEK1 or WT JNK1 expression, it is likely that multiple signaling pathways downstream of FAK contribute to uPA expression, cell invasion and metastasis.…”

“…Owing to these concerns, recent studies have used RNAi to reduce FAK expression. In human MDA-231 breast carcinoma cells, anti-FAK RNAi resulted in the inhibition of lung metastasis after orthotopic implantation in nude mice (Benlimame et al, 2005).…”

SLK-mediated phosphorylation of paxillin is required for focal adhesion turnover and cell migration

“…Additionally, aberrant trafficking of integrins to the leading edge has been documented to activate the matrix-degrading proteases such as matrix metalloproteinases (MMPs) and plasmin, required for degradation of the ECM and subsequent cell invasion [38,40]. Moreover, stimulation of cells with the growth factor heregulin (HRG), has been shown to affect the expression and serine phosphorylation status of the focal adhesion protein paxillin, resulting in both the induction of morphological changes in cell shape as well as the stimulation of cell scattering in the breast cancer epithelial cell line, MCF-7 [41][42][43]. Paxillin has also been implicated in contributing to tumor invasiveness and metastasis in breast cancer, non-small cell lung cancer, prostate cancer and osteosarcomas [41][42][43].…”

“…Moreover, stimulation of cells with the growth factor heregulin (HRG), has been shown to affect the expression and serine phosphorylation status of the focal adhesion protein paxillin, resulting in both the induction of morphological changes in cell shape as well as the stimulation of cell scattering in the breast cancer epithelial cell line, MCF-7 [41][42][43]. Paxillin has also been implicated in contributing to tumor invasiveness and metastasis in breast cancer, non-small cell lung cancer, prostate cancer and osteosarcomas [41][42][43]. Lastly, over-expression of FAK has been documented in invasive and metastatic breast, colon, thyroid and prostate cancers [44,45].…”

“…Overexpression of HER2 (ErbB2 (mouse); Neu (rat); HER2 (human), a receptor tyrosine kinase (RTK) that is a member of the epidermal growth factor (EGF) family, is associated with increased progression and metastasis in human breast cancer [43,118,147]. Approximately, 25-30% of breast cancer patients overexpressing HER2 present with a more aggressive clinical course and decreased disease-free survival due to more invasive tumors [148,149].…”