A novel role of ERK5 in integrin-mediated cell adhesion and motility in cancer cells via Fak signaling.
In metastatic cancer, high expression levels of vitronectin (VN) receptors (integrins), FAK, and ERK5 are reported. We hypothesized that integrin-mediated ERK5 activation via FAK may play a pivotal role in cell adhesion, motility, and metastasis. ERK5 and FAK phosphorylation when metastatic MDA-MB-231 and PC-3 cells were plated on VN was enhanced. Further experiments showed co-immunoprecipitation of integrins beta1, alpha V beta 3, or alpha V beta 5 with ERK5 and FAK. To gain better insight into the mechanism of ERK5, FAK, and VN receptors in cell adhesion and motility, we performed loss-of-function experiments using integrin blocking antibodies, and specific mutants of FAK and ERK5. Ectopic expression of dominant negative ERK5/AEF decreased ERK5 and FAK (Y397) phosphorylation, cell adhesion, and haptotactic motility (micromotion) on VN. Additionally, DN FAK expression attenuated ERK5 phosphorylation, cell adhesion, and motility. This study documents the novel finding that in breast and prostate cancer cells, ERK5 is a critical target of FAK in cell adhesion signaling. Using different cancer cells, our experiments unveil a novel mechanism by which VN receptors and FAK could promote cancer metastasis via ERK5 activation.
Sawhney
Rajinder S
RS
Department of Pharmacology & Toxicology, SUNY at Buffalo, Buffalo, New York, USA. rsawhney@buffalo.edu
Liu
Wensheng
W
Brattain
Michael G
MG
D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism; D002448:Cell Adhesion / Q000502:physiology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology*; D004789:Enzyme Activation; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000235:genetics / Q000378:metabolism; D019012:Integrin beta1 / Q000378:metabolism; D016023:Integrins / Q000235:genetics / Q000378:metabolism*; D048054:Mitogen-Activated Protein Kinase 7 / Q000235:genetics / Q000378:metabolism*; D009369:Neoplasms / Q000378:metabolism* / Q000473:pathology; D019030:Receptors, Vitronectin / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D019096:Vitronectin / Q000378:metabolism
D000911:Antibodies, Monoclonal; D039302:Integrin alphaVbeta3; D019012:Integrin beta1; D016023:Integrins; D019030:Receptors, Vitronectin; D019096:Vitronectin; C064660:integrin alphaVbeta5; D051416:Focal Adhesion Protein-Tyrosine Kinases; D048054:Mitogen-Activated Protein Kinase 7