Prometastatic NEDD9 Regulates Individual Cell Migration via Caveolin-1-Dependent Trafficking of Integrins.

Autor:	Kozyulina PY; Department of Biochemistry, School of Medicine, West Virginia University, Morgantown, West Virginia. Institute of Cytology Russian Academy of Sciences, St. Petersburg, Russia., Loskutov YV; Mary Babb Randolph Cancer Center, School of Medicine, West Virginia University, Morgantown, West Virginia., Kozyreva VK; Mary Babb Randolph Cancer Center, School of Medicine, West Virginia University, Morgantown, West Virginia., Rajulapati A; Mary Babb Randolph Cancer Center, School of Medicine, West Virginia University, Morgantown, West Virginia., Ice RJ; Mary Babb Randolph Cancer Center, School of Medicine, West Virginia University, Morgantown, West Virginia., Jones BC; Department of Biochemistry, School of Medicine, West Virginia University, Morgantown, West Virginia., Pugacheva EN; Department of Biochemistry, School of Medicine, West Virginia University, Morgantown, West Virginia. Mary Babb Randolph Cancer Center, School of Medicine, West Virginia University, Morgantown, West Virginia. epugacheva@hsc.wvu.edu.
Jazyk:	angličtina
Zdroj:	Molecular cancer research : MCR [Mol Cancer Res] 2015 Mar; Vol. 13 (3), pp. 423-38. Date of Electronic Publication: 2014 Oct 15.
DOI:	10.1158/1541-7786.MCR-14-0353
Abstrakt:	Unlabelled: The dissemination of tumor cells relies on efficient cell adhesion and migration, which in turn depends upon endocytic trafficking of integrins. In the current work, it was found that depletion of the prometastatic protein, NEDD9, in breast cancer cells results in a significant decrease in individual cell migration due to impaired trafficking of ligand-bound integrins. NEDD9 deficiency does not affect the expression or internalization of integrins but heightens caveolae-dependent trafficking of ligand-bound integrins to early endosomes. Increase in mobility of ligand-bound integrins is concomitant with an increase in tyrosine phosphorylation of caveolin-1 (CAV1) and volume of CAV1-vesicles. NEDD9 directly binds to CAV1 and colocalizes within CAV1 vesicles. In the absence of NEDD9, the trafficking of ligand-bound integrins from early to late endosomes is impaired, resulting in a significant decrease in degradation of ligand-integrin complexes and an increase in recycling of ligand-bound integrins from early endosomes back to the plasma membrane without ligand disengagement, thus leading to low adhesion and migration. Reexpression of NEDD9 or decrease in the amount of active, tyrosine 14 phosphorylated (Tyr14) CAV1 in NEDD9-depleted cells rescues the integrin trafficking deficiency and restores cellular adhesion and migration capacity. Collectively, these findings indicate that NEDD9 orchestrates trafficking of ligand-bound integrins through the attenuation of CAV1 activity. Implications: This study provides valuable new insight into the potential therapeutic benefit of NEDD9 depletion to reduce dissemination of tumor cells and discovers a new regulatory role of NEDD9 in promoting migration through modulation of CAV1-dependent trafficking of integrins. (©2014 American Association for Cancer Research.)
Databáze:	MEDLINE
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