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1.
Am J Pathol ; 171(2): 452-62, 2007 Aug.
Article in English | MEDLINE | ID: mdl-17620366

ABSTRACT

Acute renal failure due to ischemia/reperfusion involves disruption of integrin-mediated cellular adhesion and activation of the extracellular signal-regulated kinase (ERK) pathway. The dynamics of focal adhesion organization and phosphorylation during ischemia/reperfusion in relation to ERK activation are unknown. In control kidneys, protein tyrosine-rich focal adhesions, containing focal adhesion kinase, paxillin, and talin, were present at the basolateral membrane of tubular cells and colocalized with short F-actin stress fibers. Unilateral renal ischemia/reperfusion caused a reversible protein dephosphorylation and loss of focal adhesions. The focal adhesion protein phosphorylation rebounded in a biphasic manner, in association with increased focal adhesion kinase, Src, and paxillin tyrosine phosphorylation. Preceding phosphorylation of these focal adhesion proteins, reperfusion caused increased phosphorylation of ERK. The specific mitogen-activated protein kinase kinase 1/2 inhibitor U0126 prevented ERK activation and attenuated focal adhesion kinase, paxillin, and Src phosphorylation, focal adhesion restructuring, and ischemia/reperfusion-induced renal injury. We propose a model whereby ERK activation enhanced protein tyrosine phosphorylation during ischemia/reperfusion, thereby driving the dynamic dissolution and restructuring of focal adhesions and F-actin cytoskeleton during reperfusion and renal injury.


Subject(s)
Extracellular Signal-Regulated MAP Kinases/metabolism , Focal Adhesions/pathology , Kidney/pathology , Reperfusion Injury/physiopathology , Actins/metabolism , Animals , Blotting, Western , Butadienes/pharmacology , Enzyme Activation/drug effects , Extracellular Signal-Regulated MAP Kinases/antagonists & inhibitors , Focal Adhesion Protein-Tyrosine Kinases/metabolism , Focal Adhesions/metabolism , Immunohistochemistry , Kidney/drug effects , Kidney/metabolism , MAP Kinase Signaling System/drug effects , Male , Mitogen-Activated Protein Kinase 1/antagonists & inhibitors , Mitogen-Activated Protein Kinase 1/metabolism , Mitogen-Activated Protein Kinase 3/antagonists & inhibitors , Mitogen-Activated Protein Kinase 3/metabolism , Nitriles/pharmacology , Paxillin/metabolism , Phosphorylation , Proto-Oncogene Proteins pp60(c-src)/metabolism , Rats , Rats, Wistar , Reperfusion Injury/prevention & control , Stress Fibers/metabolism , Talin/metabolism , Time Factors , Tyrosine/metabolism
2.
Cancer Res ; 65(11): 4698-706, 2005 Jun 01.
Article in English | MEDLINE | ID: mdl-15930288

ABSTRACT

An increased expression of focal adhesion kinase (FAK) in a variety of cancers is associated with a poor disease prognosis. To study the role of FAK in breast tumor growth and metastasis formation, we used conditional doxycycline-regulated expression of a dominant-negative acting splice variant of FAK, FAK-related non-kinase (FRNK), in MTLn3 mammary adenocarcinoma cells in a syngeneic Fischer 344 rat tumor and metastasis model. In cell culture, doxycycline-mediated expression of FRNK inhibited MTLn3 cell spreading and migration in association with reduced formation of focal adhesions and phosphorylation of FAK on Tyr(397), but FRNK did not cause apoptosis. Continuous expression of FRNK decreased the primary tumor growth in the mammary fat pad by 60%, which was not due to induction of apoptosis. Lung metastasis formation was almost completely prevented when FRNK was already expressed 1 day before tumor cell injection, whereas expression of FRNK 11 days after injection did not affect lung metastasis formation. FRNK expression during the first 5 days was sufficient to block metastasis formation, excluding the possibility of FRNK-induced dormancy of tumor cells. Together, these data fit with a model wherein FAK is required for breast tumor cell invasion/migration processes that take place in the early phase of metastasis formation. Our findings suggest that FAK is a good candidate for therapeutic intervention of metastasis formation.


Subject(s)
Adenocarcinoma/enzymology , Adenocarcinoma/secondary , Lung Neoplasms/enzymology , Lung Neoplasms/secondary , Mammary Neoplasms, Experimental/enzymology , Mammary Neoplasms, Experimental/pathology , Protein-Tyrosine Kinases/physiology , Adenocarcinoma/pathology , Animals , Cell Adhesion/physiology , Cell Growth Processes/physiology , Cell Line, Tumor , Cell Movement/physiology , Doxycycline/pharmacology , Focal Adhesion Kinase 1 , Focal Adhesion Protein-Tyrosine Kinases , Hemagglutinins/biosynthesis , Hemagglutinins/genetics , Neoplasm Metastasis , Phosphorylation , Protein-Tyrosine Kinases/biosynthesis , Protein-Tyrosine Kinases/genetics , Protein-Tyrosine Kinases/metabolism , Rats , Rats, Inbred F344
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