Abstract
BackgroundThe molecular biology of renal cell carcinoma (RCC) is complex and not fully understood. We have recently found that the expression of the receptor tyrosine kinase Axl in the RCC tumors independently correlates with survival of the patients.Principal FindingsHere, we have investigated the role of Axl and its ligand Gas6, the vitamin-K dependent protein product of the growth arrest-specific gene 6, in clear cell RCC (ccRCC) derived cells. The Axl protein was highly expressed in ccRCC cells deficient in functional von Hippel-Lindau (VHL) protein, a tumor suppressor gene often inactivated in ccRCC. VHL reconstituted cells expressed decreased levels of Axl protein, but not Axl mRNA, suggesting VHL to regulate Axl expression. Gas6-mediated activation of Axl in ccRCC cells resulted in Axl phosphorylation, receptor down-regulation, decreased cell-viability and migratory capacity. No effects of the Gas6/Axl system could be detected on invasion. Moreover, in ccRCC tumor tissues, Axl was phosphorylated and Gas6 γ-carboxylated, suggesting these molecules to be active in vivo.SignificanceThese results provide novel information regarding the complex function of the Gas6/Axl system in ccRCC.
Highlights
The receptor tyrosine kinases (RTKs) constitute a superfamily of transmembrane proteins that relays signals from extracellular growth factors into the cell. [1,2]The TAM subfamily of RTKs contains the receptors Axl, Tyro3, and Mer [3,4]
Since Gas6 ligand only is functional and can stimulate Axl properly when correctly c-carboxylated processed by Vitamin K [32], we examined whether Gas6 was present and c-carboxylated in the matched ccRCC biopsies
The Axl protein levels remained low when the von Hippel-Lindau (VHL) reconstituted cells were grown at hypoxia (1% oxygen) and reactivate the hypoxic response due to stabilization of HIF-2a (Fig. 5B). These results suggest that Axl is not a direct HIF2a gene target (HIF-1a is not expressed in 786-O cells [34,35]) Axl protein expression was high in ccRCC cell lines with defective VHL protein compared to Caki-2 [36], a ccRCC cell line with papillary renal cell carcinoma (RCC) characteristic and functional VHL (Fig. 5C)
Summary
The receptor tyrosine kinases (RTKs) constitute a superfamily of transmembrane proteins that relays signals from extracellular growth factors into the cell. The TAM subfamily of RTKs contains the receptors Axl, Tyro, and Mer [3,4]. They have in common a unique extracellular domain composed of two N-terminal immunoglobulin-like domains and two fibronectin type III repeats similar to the structure of neural cell adhesion molecules (NCAMs). Gas in general serve as a mitogen and survival factor that protects cells from serum starvation-induced apoptosis [10]. We have recently found that the expression of the receptor tyrosine kinase Axl in the RCC tumors independently correlates with survival of the patients
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