Cross-Talk between Receptor Tyrosine Kinases AXL and ERBB3 Regulates Invadopodia Formation in Melanoma Cells.

Autor:	Revach OY; Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel., Sandler O; Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel., Samuels Y; Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel., Geiger B; Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel. benny.geiger@weizmann.ac.il.
Jazyk:	angličtina
Zdroj:	Cancer research [Cancer Res] 2019 May 15; Vol. 79 (10), pp. 2634-2648. Date of Electronic Publication: 2019 Mar 26.
DOI:	10.1158/0008-5472.CAN-18-2316
Abstrakt:	The invasive phenotype of metastatic cancer cells is accompanied by the formation of actin-rich invadopodia, which adhere to the extracellular matrix and degrade it. In this study, we explored the role of the tyrosine kinome in the formation of invadopodia in metastatic melanoma cells. Using a microscopy-based siRNA screen, we identified a series of regulators, the knockdown of which either suppresses (e.g., TYK2, IGFR1, ERBB3, TYRO3, FES, ALK, PTK7) or enhances (e.g., ABL2, AXL, CSK) invadopodia formation and function. Notably, the receptor tyrosine kinase AXL displayed a dual regulatory function, where both depletion or overexpression enhanced invadopodia formation and activity. This apparent contradiction was attributed to the capacity of AXL to directly stimulate invadopodia, yet its suppression upregulates the ERBB3 signaling pathway, which can also activate core invadopodia regulators and enhance invadopodia function. Bioinformatic analysis of multiple melanoma cell lines points to an inverse expression pattern of AXL and ERBB3. High expression of AXL in melanoma cells is associated with high expression of invadopodia components and an invasive phenotype. These results provide new insights into the complexity of metastasis-promoting mechanisms and suggest that targeting of multiple invadopodia signaling networks may serve as a potential anti-invasion therapy in melanoma. SIGNIFICANCE: These findings uncover a unique interplay between AXL and ERBB3 in invadopodia regulation that points to the need for combined therapy in order to prevent invadopodia-mediated metastasis in melanoma. (©2019 American Association for Cancer Research.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu