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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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FAK is required for ErbB-induced tumor progression and tumor invasion in vivo, whereas the restoration of FAK in FAK−/− cells rescued the deficiency in tumor invasion. (A) Tumor growth kinetics after subcutaneous implantation of cells into the flank of Scid mice. (B) Tumor growth kinetics after subcutaneous implantation of FAK−/−-2/3 and FAK−/−-2/3–reconstituted cells (FAK−/−-2/3–FAK); FAK+/+-2/3 cells were used as positive controls. Tumor growth was monitored over time as indicated in Materials and methods. Each point represents the mean of five to eight mice ± SEM. (C) Quantification of lung surface metastases induced by intravenous cell administration. (a) Mean surface lung metastases (n = 8–10) ± SEM. (b) Representative lungs from mice inoculated with FAK−/− and FAK+/+ control cells (expressing empty retroviral particles) and cells overexpressing ErbB-2, -3, or -2/3 receptors. (D) Mean lung metastases (n = 8) ± SEM (error bars) induced by FAK−/−-2/3 or FAK-reconstituted FAK−/−-2/3 (FAK−/−-2/3–FAK). FAK+/+-2/3 cells were used as positive controls.
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fig3: FAK is required for ErbB-induced tumor progression and tumor invasion in vivo, whereas the restoration of FAK in FAK−/− cells rescued the deficiency in tumor invasion. (A) Tumor growth kinetics after subcutaneous implantation of cells into the flank of Scid mice. (B) Tumor growth kinetics after subcutaneous implantation of FAK−/−-2/3 and FAK−/−-2/3–reconstituted cells (FAK−/−-2/3–FAK); FAK+/+-2/3 cells were used as positive controls. Tumor growth was monitored over time as indicated in Materials and methods. Each point represents the mean of five to eight mice ± SEM. (C) Quantification of lung surface metastases induced by intravenous cell administration. (a) Mean surface lung metastases (n = 8–10) ± SEM. (b) Representative lungs from mice inoculated with FAK−/− and FAK+/+ control cells (expressing empty retroviral particles) and cells overexpressing ErbB-2, -3, or -2/3 receptors. (D) Mean lung metastases (n = 8) ± SEM (error bars) induced by FAK−/−-2/3 or FAK-reconstituted FAK−/−-2/3 (FAK−/−-2/3–FAK). FAK+/+-2/3 cells were used as positive controls.

Mentions: Parental FAK−/− and FAK+/+ cells exhibit no apparent morphological changes that reflect cell transformation, and they lack the ability to grow on soft agar and form tumors in immunocompromised mice (see Fig. 3). Neither control FAK+/+ nor FAK−/− cells expressing empty retroviral particles that were used to express ErbB receptors formed colonies in soft agar. In contrast, FAK+/+-2 and -2/3 cells, but not FAK+/+-3 or any FAK−/−–ErbB-expressing cells, were able to grow on soft agar and form large foci; the coexpression of ErbB-2 with -3 resulted in strong oncogenic transformation compared with ErbB-2 alone (Fig. 2 B and Fig. S2 A, available at http://www.jcb.org/cgi/content/full/jcb.200504124/DC1).


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)

FAK is required for ErbB-induced tumor progression and tumor invasion in vivo, whereas the restoration of FAK in FAK−/− cells rescued the deficiency in tumor invasion. (A) Tumor growth kinetics after subcutaneous implantation of cells into the flank of Scid mice. (B) Tumor growth kinetics after subcutaneous implantation of FAK−/−-2/3 and FAK−/−-2/3–reconstituted cells (FAK−/−-2/3–FAK); FAK+/+-2/3 cells were used as positive controls. Tumor growth was monitored over time as indicated in Materials and methods. Each point represents the mean of five to eight mice ± SEM. (C) Quantification of lung surface metastases induced by intravenous cell administration. (a) Mean surface lung metastases (n = 8–10) ± SEM. (b) Representative lungs from mice inoculated with FAK−/− and FAK+/+ control cells (expressing empty retroviral particles) and cells overexpressing ErbB-2, -3, or -2/3 receptors. (D) Mean lung metastases (n = 8) ± SEM (error bars) induced by FAK−/−-2/3 or FAK-reconstituted FAK−/−-2/3 (FAK−/−-2/3–FAK). FAK+/+-2/3 cells were used as positive controls.
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Related In: Results  -  Collection

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

fig3: FAK is required for ErbB-induced tumor progression and tumor invasion in vivo, whereas the restoration of FAK in FAK−/− cells rescued the deficiency in tumor invasion. (A) Tumor growth kinetics after subcutaneous implantation of cells into the flank of Scid mice. (B) Tumor growth kinetics after subcutaneous implantation of FAK−/−-2/3 and FAK−/−-2/3–reconstituted cells (FAK−/−-2/3–FAK); FAK+/+-2/3 cells were used as positive controls. Tumor growth was monitored over time as indicated in Materials and methods. Each point represents the mean of five to eight mice ± SEM. (C) Quantification of lung surface metastases induced by intravenous cell administration. (a) Mean surface lung metastases (n = 8–10) ± SEM. (b) Representative lungs from mice inoculated with FAK−/− and FAK+/+ control cells (expressing empty retroviral particles) and cells overexpressing ErbB-2, -3, or -2/3 receptors. (D) Mean lung metastases (n = 8) ± SEM (error bars) induced by FAK−/−-2/3 or FAK-reconstituted FAK−/−-2/3 (FAK−/−-2/3–FAK). FAK+/+-2/3 cells were used as positive controls.
Mentions: Parental FAK−/− and FAK+/+ cells exhibit no apparent morphological changes that reflect cell transformation, and they lack the ability to grow on soft agar and form tumors in immunocompromised mice (see Fig. 3). Neither control FAK+/+ nor FAK−/− cells expressing empty retroviral particles that were used to express ErbB receptors formed colonies in soft agar. In contrast, FAK+/+-2 and -2/3 cells, but not FAK+/+-3 or any FAK−/−–ErbB-expressing cells, were able to grow on soft agar and form large foci; the coexpression of ErbB-2 with -3 resulted in strong oncogenic transformation compared with ErbB-2 alone (Fig. 2 B and Fig. S2 A, available at http://www.jcb.org/cgi/content/full/jcb.200504124/DC1).

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