Faculty Collaboration Database

Focal adhesion kinase, a downstream mediator of Raf-1 signaling, suppresses cellular adhesion, migration, and neuroendocrine markers in BON carcinoid cells. Mol Cancer Res 2010 May;8(5):775-82

Date

04/22/2010

Pubmed ID

20407018

Pubmed Central ID

PMC2872724

DOI

10.1158/1541-7786.MCR-09-0525

Scopus ID

2-s2.0-77952936178 (requires institutional sign-in at Scopus site)   12 Citations

Abstract

We have recently reported that activation of the Raf-1/mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) kinase 1/2 (MEK1/2)/ERK1/2 signaling cascade in gastrointestinal carcinoid cell line (BON) alters cellular morphology and neuroendocrine phenotype. The mechanisms by which Raf-1 mediates these changes in carcinoid cells are unclear. Here, we report that activation of the Raf-1 signaling cascade in BON cells induced the expression of focal adhesion kinase (FAK) protein, suppressed the production of neuroendocrine markers, and resulted in significant decreases in cellular adhesion and migration. Importantly, inactivation of MEK1/2 by 1,4-diamino-2,3-dicyano-1,4-bis[2-aminophenylthio]butadiene or abolition of FAK induction in Raf-1-activated BON cells by targeted siRNA led to reversal of the Raf-1-mediated reduction in neuroendocrine markers and cellular adhesion and migration. Phosphorylation site-specific antibodies detected the phosphorylated FAK(Tyr407), but not FAK(Tyr397), in these Raf-1-activated cells, indicating that FAK(Tyr407) may be associated with changes in the neuroendocrine phenotype. Overexpression of constitutively active FAK plasmids (wild-type FAK or FAK(Tyr397) mutant) into BON cells reduced neuroendocrine markers, whereas the FAK(Tyr407) mutant plasmid did not show any decrease in the levels of neuroendocrine markers, indicating that phosphorylation of FAK at the Tyr(407) residue may be important for these effects. Our results showed for the first time that FAK is an essential downstream effector of the Raf-1/MEK1/2/ERK1/2 signaling cascade and negatively regulated the neuroendocrine and metastatic phenotype in BON cells.

Author List

Ning L, Chen H, Kunnimalaiyaan M

MESH terms used to index this publication - Major topics in bold

Biomarkers, Tumor
Carcinoid Tumor
Cell Adhesion
Cell Line, Tumor
Cell Migration Inhibition
Focal Adhesion Protein-Tyrosine Kinases
Gastrointestinal Neoplasms
Gene Expression Regulation, Enzymologic
Gene Expression Regulation, Neoplastic
Humans
MAP Kinase Kinase 1
Mitogen-Activated Protein Kinase 3
Neoplasm Metastasis
Neuroendocrine Cells
Pancreatic Neoplasms
Phenotype
Proto-Oncogene Proteins c-raf
Signal Transduction