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

Benlimame N, He Q, Jie S, Xiao D, Xu YJ, Loignon M, Schlaepfer DD, Alaoui-Jamali MA - J. Cell Biol. (2005)

Bottom Line: The overexpression of members of the ErbB tyrosine kinase receptor family has been associated with cancer progression.This colocalization requires intact FAK.In summary, distinct FAK signaling has an essential function in ErbB-induced oncogenesis and invasiveness.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, Lady Davis Institute of the Sir Mortimer B. Davis Jewish General Hospital, McGill University, Montreal, Quebec H3T 1E2, Canada.

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.

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Related in: MedlinePlus

ErbB-2 colocalizes with FAK at focal adhesions in invasive breast cancer cells. Cells were fixed, permeabilized, and subjected to confocal microscopy after double immunostaining with anti–ErbB-2 and anti-FAK antibodies followed by appropriate secondary antibodies conjugated either to Cy2 or Texas red (left) or conjugated to AMCA and Texas red (middle) to detect ErbB-2 and FAK, respectively. The panels show a strong labeling of FAK, which was localized to cell extensions and ventral focal contact sites within the cells. For all cell lines, dual-color merged confocal images reveal a partial colocalization of ErbB-2 with FAK (arrows). Bars, 50 μm.
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fig8: ErbB-2 colocalizes with FAK at focal adhesions in invasive breast cancer cells. Cells were fixed, permeabilized, and subjected to confocal microscopy after double immunostaining with anti–ErbB-2 and anti-FAK antibodies followed by appropriate secondary antibodies conjugated either to Cy2 or Texas red (left) or conjugated to AMCA and Texas red (middle) to detect ErbB-2 and FAK, respectively. The panels show a strong labeling of FAK, which was localized to cell extensions and ventral focal contact sites within the cells. For all cell lines, dual-color merged confocal images reveal a partial colocalization of ErbB-2 with FAK (arrows). Bars, 50 μm.

Mentions: To confirm the colocalization of ErbB and FAK in SKBR3, T47D, MDA-231-M2, and MCF7-M4, the ErbB-2 receptor was coimmunolabeled with antibodies against ErbB-2 and FAK. Fig. 8 shows that both ErbB-2 and FAK colocalize to cell protrusions in all of these cells. Double labeling of ErbB-2 and FAK indicate that cells with ErbB-2 overexpression exhibit a strong colocalization of FAK with ErbB-2 at the cell lamellipodia. In all cases, confocal microscopy indicates that ErbB and FAK localization is partial.


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

Benlimame N, He Q, Jie S, Xiao D, Xu YJ, Loignon M, Schlaepfer DD, Alaoui-Jamali MA - J. Cell Biol. (2005)

ErbB-2 colocalizes with FAK at focal adhesions in invasive breast cancer cells. Cells were fixed, permeabilized, and subjected to confocal microscopy after double immunostaining with anti–ErbB-2 and anti-FAK antibodies followed by appropriate secondary antibodies conjugated either to Cy2 or Texas red (left) or conjugated to AMCA and Texas red (middle) to detect ErbB-2 and FAK, respectively. The panels show a strong labeling of FAK, which was localized to cell extensions and ventral focal contact sites within the cells. For all cell lines, dual-color merged confocal images reveal a partial colocalization of ErbB-2 with FAK (arrows). Bars, 50 μm.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2171271&req=5

fig8: ErbB-2 colocalizes with FAK at focal adhesions in invasive breast cancer cells. Cells were fixed, permeabilized, and subjected to confocal microscopy after double immunostaining with anti–ErbB-2 and anti-FAK antibodies followed by appropriate secondary antibodies conjugated either to Cy2 or Texas red (left) or conjugated to AMCA and Texas red (middle) to detect ErbB-2 and FAK, respectively. The panels show a strong labeling of FAK, which was localized to cell extensions and ventral focal contact sites within the cells. For all cell lines, dual-color merged confocal images reveal a partial colocalization of ErbB-2 with FAK (arrows). Bars, 50 μm.
Mentions: To confirm the colocalization of ErbB and FAK in SKBR3, T47D, MDA-231-M2, and MCF7-M4, the ErbB-2 receptor was coimmunolabeled with antibodies against ErbB-2 and FAK. Fig. 8 shows that both ErbB-2 and FAK colocalize to cell protrusions in all of these cells. Double labeling of ErbB-2 and FAK indicate that cells with ErbB-2 overexpression exhibit a strong colocalization of FAK with ErbB-2 at the cell lamellipodia. In all cases, confocal microscopy indicates that ErbB and FAK localization is partial.

Bottom Line: The overexpression of members of the ErbB tyrosine kinase receptor family has been associated with cancer progression.This colocalization requires intact FAK.In summary, distinct FAK signaling has an essential function in ErbB-induced oncogenesis and invasiveness.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, Lady Davis Institute of the Sir Mortimer B. Davis Jewish General Hospital, McGill University, Montreal, Quebec H3T 1E2, Canada.

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.

Show MeSH
Related in: MedlinePlus