Determinants for transformation induced by the Axl receptor tyrosine kinase

Burchert, Andreas; Attar, Eyal C.; McCloskey, Patrick; Fridell, Yih-Woei C.; Liu, Edison T.

doi:10.1038/sj.onc.1201865

Cited by 54 publications

(39 citation statements)

References 32 publications

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“…Various studies have demonstrated roles of GAS6/AXL in regulating cell growth and survival in normal and cancer cells (Stitt et al, 1995;Wimmel et al, 2001). AXL is characterized by a unique extracellular composition consisting of immunoglobulin-like and fibronectin-type III-like domains, which are also found in adhesion molecules of the cadherin and immunoglobulin superfamily, therefore suggesting that AXL might regulate cell adhesion (Burchert et al, 1998). Other evidence is consistent with roles of AXL in tumor cell invasion, metastasis and survival (Jacob et al, 1999;Holland et al, 2005;Mahadevan et al, 2007).…”

Section: Introductionmentioning

confidence: 70%

AXL regulates mesothelioma proliferation and invasiveness

et al. 2010

Oncogene

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Mesothelioma is an asbestos-associated and notoriously chemotherapy-resistant neoplasm. Activation of the receptor tyrosine kinases (RTKs), epidermal growth factor receptor and MET, has been described in subsets of mesothelioma, suggesting that TKs might represent therapeutic targets in this highly lethal disease. We employed proteomic screening by phosphotyrosine immunoaffinity purification and tandem mass spectrometry to characterize RTK activation in mesothelioma cell lines. These assays demonstrated expression and activation of the AXL protein, which is an RTK with known oncogenic properties in non-mesothelial cancer types. AXL was expressed and activated strongly in 8 of 9 mesothelioma cell lines and 6 of 12 mesothelioma biopsies, including each of 12 mesotheliomas with spindle-cell histology. Somatic AXL mutations were not found, but all mesotheliomas expressed an alternatively spliced AXL transcript with in-frame deletion of exon 10, and six of seven mesothelioma cell lines expressed the AXL ligand, growth arrest-specific 6 (GAS6). GAS6 expression appeared to be functionally relevant, as indicated by modulation of AXL tyrosine phosphorylation by knockdown of endogeneous GAS6, and by administration of exogenous GAS6. AXL silencing by lentivirus-mediated short hairpin RNA suppressed mesothelioma migration and cellular proliferation due to G1 arrest. The AXL inhibitor DP-3975 inhibited cell migration and proliferation in mesotheliomas with strong AXL activation. DP-3975 response in these tumors was characterized by inhibition of PI3-K/AKT/mTOR and RAF/MAPK signaling. AXL inhibition suppressed mesothelioma anchorage-independent growth, with reduction in colony numbers and size. These studies suggest that AXL inhibitors warrant clinical evaluation in mesothelioma.

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Section: Introductionmentioning

confidence: 70%

AXL regulates mesothelioma proliferation and invasiveness

et al. 2010

Oncogene

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“…In the present study, we confirm that overexpression of MZF1 is tumorigenic, and for the first time, we report that MZF1 induces tumor growth and metastasis through the transactivation of Axl, thus adding to the molecular targets and mechanisms that can mediate an oncogenic potential of MZF1 in epithelialderived tissues. Axl has been reported as a transforming gene (21) that is overexpressed in several tumors (22)(23)(24)(25)(26)(27), and the Gas6/Axl signaling pathway is known to induce cell proliferation, antiapoptosis, migration, invasion, and angiogenic processes, which are most likely mediated through Ras, Src, mitogen-activated protein kinase/extracellular signal-regulated kinase, phosphoinositide 3-kinase/Akt, and NF-κB signaling pathways (14,15,19,29,31,32,(44)(45)(46)(47)(48)(49). However, still further studies are needed to enhance the understanding of the downstream components of the Gas6/Axl signaling axis in tumor formation.…”

Section: Discussionmentioning

confidence: 99%

“…Intracellular signaling of Axl is also activated by its homophilic and heterophilic interactions (19), mediated mainly by a multisubstrate docking site (20). Overexpression of Axl can transform fibroblasts even in the absence of a ligand (21), this is at least in part being mediated by Gas6/Axl-induced activation of mitogen-activated protein kinase/extracellular signal-regulated kinase and phosphoinositide 3-kinase signaling. Following its identification in myeloid leukemia, Axl overexpression has been reported in several types of human solid cancers (22)(23)(24)(25)(26)(27).…”

Section: Introductionmentioning

confidence: 99%

Myeloid Zinc Finger 1 Induces Migration, Invasion, and In vivo Metastasis through Axl Gene Expression in Solid Cancer

Mudduluru

Vajkoczy

Allgayer

2010

Molecular Cancer Research

118

129

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Myeloid zinc finger 1 (MZF1) is a member of the SCAN domain family transcription factors that form dimers through their highly conserved SCAN motifs. Silencing of MZF1 inhibits cell proliferation, and abnormal expression of MZF1 results in cancer development. However, a potential role of MZF1 in metastasis remains unclear. Axl is a receptor tyrosine kinase and was first identified as a transforming gene in chronic myeloid leukemia. Axl overexpression induces proliferation, migration, and invasion and is highly expressed in different human cancers. In this study, we show that overexpression of MZF1 induces migration and invasion in colorectal (Rko, SW480) and cervical (HeLa) cancer cells. In addition, we show that MZF1 binds to the Axl promoter, transactivates promoter activity, and enhances Axl-mRNA and protein expression in a dose-dependent manner. In vitro, sh-RNA knockdown of Axl reduced MZF1-induced migration and invasion in HeLa and Rko cells (P = 0.05). Additionally, Rko cells overexpressing MZF1 showed increased tumor formation and liver metastasis in the chicken-embryo-metastasis assay in vivo. Furthermore, the expression of MZF1 and Axl was significantly higher in resected colorectal tumors compared with corresponding normal tissues (P = 0.02; P = 0.05), and MZF1 expression was positively correlated with Axl gene expression in tumor tissues (P < 0.01). Taken together, this is the first study to show that MZF1 induces invasion and in vivo metastasis in colorectal and cervical cancer, at least in part by regulating Axl gene expression. Mol Cancer Res; 8(2); 159-69. ©2010 AACR.

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“…Overexpression of Axl can transform fibroblasts even in the absence of a ligand (Burchert et al, 1998). Axl is known to induce cell survival (Melaragno et al, 2004;van Ginkel et al, 2004), proliferation (Stenhoff et al, 2004;Sainaghi et al, 2005), stimulation of cell migration and cell-cell adhesion (McCloskey et al, 1997).…”

Section: Introductionmentioning

confidence: 99%

Regulation of Axl receptor tyrosine kinase expression by miR-34a and miR-199a/b in solid cancer

et al. 2011

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Axl is a receptor that induces proliferation, migration and invasion in cancer. In this study, we show that specific microRNAs (miRNAs) target the 3 0 -UTR of Axl. Luciferase-reporter assays with wild-type and deleted miR-34 and miR-199a/b seed sequences of Axl 3 0 -UTR confirmed the specificity of targeting. An inverse correlation between Axl protein and miR-34a expression in a panel of non-small cell lung cancer (NSCLC), colorectal cancer (CRC) and breast cancer (BRC) cell lines was observed, while miR-199a/b expression was completely suppressed. Pre-miR transfection inhibited in vitro migration and invasion and, in vivo, reduced the number of distant lung-or liver-metastases in a chorion-allantoicmembrane (CAM) assay. Moreover, methylation-specific PCR on bisulfite-converted DNA obtained from the cell lines showed that the miR-34a promoter methylation status was inversely correlated with its expression, and that miR-199a/b promoter regions were methylated in all cells tested. In a panel of NSCLC tissues (n ¼ 44), miR34a and miR-199a/b were found to be downregulated and significantly co-expressed. A lower expression of all three miRs was significantly associated with squamous histotypes, and, in a preliminary series, NSCLC patients with miR-34a upregulation showed a positive association towards a longer survival. These results indicate that Axl receptor expression can be regulated by miR-34a and miR-199a/b, which are suppressed by promoter methylation in solid cancer cells.

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Determinants for transformation induced by the Axl receptor tyrosine kinase

Cited by 54 publications

References 32 publications

AXL regulates mesothelioma proliferation and invasiveness

AXL regulates mesothelioma proliferation and invasiveness

Myeloid Zinc Finger 1 Induces Migration, Invasion, and In vivo Metastasis through Axl Gene Expression in Solid Cancer

Regulation of Axl receptor tyrosine kinase expression by miR-34a and miR-199a/b in solid cancer

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