Gas6 Induces Growth, β-Catenin Stabilization, and T-Cell Factor Transcriptional Activation in Contact-Inhibited C57 Mammary Cells

Abstract

Gas6 is a growth factor related to protein S that was identified as the ligand for the Axl receptor tyrosine kinase (RTK) family. In this study, we show that Gas6 induces a growth response in a cultured mammalian mammary cell line, C57MG. The presence of Gas6 in the medium induces growth after confluence and similarly causes cell cycle reentry of density-inhibited C57MG cells. We show that Axl RTK but not Rse is efficiently activated by Gas6 in density-inhibited C57MG cells. We have analyzed the signaling required for the Gas6 proliferative effect and found a requirement for PI3K-, S6K-, and Ras-activated pathways. We also demonstrate that Gas6 activates Akt and concomitantly inhibits GSK3 activity in a wortmannin-dependent manner. Interestingly, Gas6 induces up-regulation of cytosolic ␤-catenin, while membrane-associated ␤-catenin remains unaffected. Stabilization of ␤-catenin in C57MG cells is correlated with activation of a T-cell factor (TCF)-responsive transcriptional element. We thus provide evidence that Gas6 is mitogenic and induces ␤-catenin proto-oncogene stabilization and subsequent TCF/Lef transcriptional activation in a mammary system. These results suggest that Gas6-Axl interaction, through stabilization of ␤-catenin, may have a role in mammary development and/or be involved in the progression of mammary tumors.

Transient activation of FOXN1 in keratinocytes induces a transcriptional programme that promotes terminal differentiation: contrasting roles of FOXN1 and Akt

“…Gas6 has been shown to activate Akt in several different cell types (Goruppi et al, 2001;Valverde et al, 2004). Consistent with these findings, addition of 400 ng/ml recombinant Gas6 resulted in a moderate increase in activated Akt, detected with an antibody to serine 473 phosphorylated Akt (phospho-Akt 473 ), in keratinocytes grown under serum-and growth-factor-free conditions (Fig.…”

Cyr61 Is Overexpressed in Gliomas and Involved in Integrin-Linked Kinase-Mediated Akt and β-Catenin-TCF/Lef Signaling Pathways

“…Several studies have found that Akt could decrease GSK-3␤ activity, but the change was not sufficient to cause translocation of ␤-catenin into the nucleus in the absence of Wnt signaling (63,64). In contrast, several other studies have found that the Akt-mediated phosphorylation and inhibition of GSK-3␤ led to accumulation and nuclear translocation of ␤-catenin (65)(66)(67)(68)(69). ILK has been reported to phosphorylate directly the serine 473 of Akt, resulting in phosphorylation and inhibition of GSK-3␤, stimulating nuclear translocation of ␤-catenin and activation of TCF/Lef transcription factor (40,42,59,70).…”

Sulfasalazine Suppresses Drug Resistance and Invasiveness of Lung Adenocarcinoma Cells Expressing AXL

“…To elucidate the mechanisms underlying AXL-associated invasiveness, ERKs, AKT/PI3K, GSK3, h-catenin, and NF-nB signaling pathways, which have been shown in previous studies (22)(23)(24)(25)(26)(27) to be involved in the regulation of AXL-mediated effects, were examined in both CL1-5F4 cells with AXL knocked down by shRNA-mediated silencing and CL1-0 cells ectopically overexpressing AXL. NF-nB activity was assessed by Western blot analysis of nuclear NF-nB p65 and cytoplasmic InBa (Fig.…”

“…In different cell types, downstream signaling of AXL has been reported to be mediated through tyrosine phosphatase SHP-2 (9), phosphatidylinositol 3-kinase (PI3K)/AKT (10,22,23), GTPases of the Rho family (24,25), glycogen synthase kinase 3 (GSK3; ref. 26), nuclear factor-nB (NF-nB; refs. 11,27), extracellular signal-regulated kinases (ERK; ref.…”