Axl receptor tyrosine kinase expression in human lung cancer cell lines correlates with cellular adhesion

Wimmel, Anja; Glitz, Dagmar; Kraus, Alison; Roeder, Jaime L.; Schuermann, Marcus

doi:10.1016/s0959-8049(01)00271-4

Cited by 107 publications

(94 citation statements)

References 23 publications

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“…Axl expression correlates with adherence of lung cancer cell lines (Wimmel et al, 2001). However, forced expression of Axl did not induce an adherent phenotype in small cell lung cancer (SCLC) cells which normally grow in suspension.…”

Section: A Migration and Invasionmentioning

confidence: 99%

TAM Receptor Tyrosine Kinases: Biologic Functions, Signaling, and Potential Therapeutic Targeting in Human Cancer

Linger¹,

Keating²,

Earp

et al. 2008

Advances in Cancer Research

607

688

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Tyro-3, Axl, and Mer constitute the TAM family of receptor tyrosine kinases (RTKs) characterized by a conserved sequence within the kinase domain and adhesion molecule-like extracellular domains. This small family of RTKs regulates an intriguing mix of processes, including cell proliferation/survival, cell adhesion and migration, blood clot stabilization, and regulation of inflammatory cytokine release. Genetic or experimental alteration of TAM receptor function can contribute to a number of disease states, including coagulopathy, autoimmune disease, retinitis pigmentosa, and cancer. In this chapter, we first provide a comprehensive review of the structure, regulation, biologic functions, and down-stream signaling pathways of these receptors. In addition, we discuss recent evidence which suggests a role for TAM receptors in oncogenic mechanisms as family members are over-expressed in a spectrum of human cancers and have prognostic significance in some. Possible strategies for targeted inhibition of the TAM family in the treatment of human cancer are described. Further research will be necessary to evaluate the full clinical implications of TAM family expression and activation in cancer.

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Section: A Migration and Invasionmentioning

confidence: 99%

TAM Receptor Tyrosine Kinases: Biologic Functions, Signaling, and Potential Therapeutic Targeting in Human Cancer

Linger¹,

Keating²,

Earp

et al. 2008

Advances in Cancer Research

607

688

View full text Add to dashboard Cite

show abstract

“…36 The antiapoptotic, cell adhesion, and chemotactic activities of Axl have been ascribed to an increased expression of Axl and its increased interaction with Gas6. 37 The invasiveness and metastasis in various cancer cell types are associated with an elevated level of Axl expression, which is also correlated with a poor prognosis of patients with various cancers such as myeloid leukemia, 34,38 metastatic lung cancer, 39,40 breast cancer, 41 and gastric cancer. 42 Use of RNAi techniques and dominant-negative receptor mutants of Axl have resulted in the growth suppression of cancer cells in a xenograft model.…”

Section: Introductionmentioning

confidence: 99%

Gain-of-Function Activity of Mutant p53 in Lung Cancer through Up-Regulation of Receptor Protein Tyrosine Kinase Axl

et al. 2012

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Abstractp53 mutations are present in up to 70% of lung cancer. Cancer cells with p53 mutations, in general, grow more aggressively than those with wildtype p53 or no p53. Expression of tumor-derived mutant p53 in cells leads to up-regulated expression of genes that may affect cell growth and oncogenesis. In our study of this aggressive phenotype, we have investigated the receptor protein tyrosine kinase Axl, which is up-regulated by p53 mutants at both RNA and protein levels in H1299 lung cancer cells expressing mutants p53-R175H, -R273H, and -D281G. Knockdown of endogenous mutant p53 levels in human lung cancer cells H1048 (p53-R273C) and H1437 (p53-R267P) led to a reduction in the level of Axl as well. This effect on Axl expression is refractory to the mutations at positions 22 and 23 of p53, suggesting that p53's transactivation domain may not play a critical role in the up-regulation of Axl gene expression. Chromatin immunoprecipitation (ChIP) assays carried out with acetylated histone antibodies demonstrated induced histone acetylation on the Axl promoter region by mutant p53. Direct mutant p53 nucleation on the Axl promoter was demonstrated by ChIP assays using antibodies against p53. The Axl promoter has a p53/p63 binding site, which however is not required for mutant p53-mediated transactivation. Knockdown of Axl by Axl-specific RNAi caused a reduction of gain-of-function (GOF) activities, reducing the cell growth rate and motility rate in lung cancer cells expressing mutant p53. This indicates that for lung cancer cell lines with mutant p53, GOF activities are mediated in part through Axl.

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“…AXL (also known as UFO/ARK/Tyro) is a RTK with oncogenic potential and transforming activity (Wimmel et al, 2001), which is stimulated by its ligand GAS6 (growth arrest-specific 6), a vitamin K-dependent growth potentiating factor (Varnum et al, 1995). AXL was first identified as a transforming gene in chronic myeloid leukemia (Janssen et al, 1991;O'Bryan et al, 1991), but is also overexpressed in metastatic colon and prostate cancer, thyroid carcinoma, breast cancer and melanoma (Quong et al, 1994;Craven et al, 1995;Ito et al, 1999;Jacob et al, 1999;Meric et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

“…AXL was first identified as a transforming gene in chronic myeloid leukemia (Janssen et al, 1991;O'Bryan et al, 1991), but is also overexpressed in metastatic colon and prostate cancer, thyroid carcinoma, breast cancer and melanoma (Quong et al, 1994;Craven et al, 1995;Ito et al, 1999;Jacob et al, 1999;Meric et al, 2002). 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).…”

Section: Introductionmentioning

confidence: 99%

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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Axl receptor tyrosine kinase expression in human lung cancer cell lines correlates with cellular adhesion

Cited by 107 publications

References 23 publications

TAM Receptor Tyrosine Kinases: Biologic Functions, Signaling, and Potential Therapeutic Targeting in Human Cancer

TAM Receptor Tyrosine Kinases: Biologic Functions, Signaling, and Potential Therapeutic Targeting in Human Cancer

Gain-of-Function Activity of Mutant p53 in Lung Cancer through Up-Regulation of Receptor Protein Tyrosine Kinase Axl

AXL regulates mesothelioma proliferation and invasiveness

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