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Axl and Its Mediated Signaling Axis in Cancer

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Mechanisms of Molecular Carcinogenesis – Volume 1

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Abstract

AXL is a receptor tyrosine kinase activated by growth arrest-specific 6 (GAS6) or by ligand-independent homophilic and/or heterophilic interactions that regulate cancer cell proliferation, survival, migration, invasion, distant metastasis, the epithelial to mesenchymal transition (EMT), angiogenesis, and drug resistance. Axl belongs to the Tyro-3, AXL, and Mer (TAM) family of receptor molecules, known to be expressed in a number of organs and cell lines with a few exceptions such as lymphocytes and granulocytes. However, inappropriate Axl upregulation leads to uncontrolled cell growth, and its abundant expression is detected in a number of cancers such as colorectal and breast tumors. The transcriptional regulation of Axl is epigenetically inhibited by CpG hyper-methylation. Furthermore, the zinc finger transcriptional factor family members Sp1 and Sp3 are the constitutive regulators of Axl. Under oncogenic conditions, AP-1 family members mainly enhance its expression. Moreover, an overexpression of MZF1 induces Axl expression and mediates the migratory and invasive behavior of cells. Axl is also posttranscriptionally regulated by the small noncoding tumor suppressor microRNAs (miRNAs) miR-34 and miR-199. A malfunction of these different regulatory mechanisms in controlling Axl expression can induce Axl expression in cancer phenotypes. In addition to aspects of its regulation, this chapter will cover details of Axl structure, its expression in diverse cancer entities, and its signaling axis in the mediation of functions related to cancer phenotypes, including cell proliferation, antiapoptotic effects, EMT, cancer metastasis, angiogenesis, and drug resistance.

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Acknowledgments

This work was supported by the German Cancer Consortium (DKTK). I thank Prof. Ulrike Stein for her suggestions, critical reading and encouragement in writing this chapter and Harikrishna Raddhakrishna, Steffen Fuchs, and Kathrina Ilm for their critical reading and discussion of this chapter.

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  1. Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, Robert-Rössle-Str. 10, 13125, Berlin, Germany

    Giridhar Mudduluru

  2. German Cancer Consortium (DKTK), Heidelberg, Germany

    Giridhar Mudduluru

  3. Experimental and Clinical Research Center, Charité University Medicine, Berlin, Berlin, Germany

    Giridhar Mudduluru

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Correspondence to Giridhar Mudduluru .

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  1. Department of Pathology, Medical Faculty, Otto von Guericke University Magdeburg, Magdeburg, Germany

    Johannes Haybaeck

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Mudduluru, G. (2017). Axl and Its Mediated Signaling Axis in Cancer. In: Haybaeck, J. (eds) Mechanisms of Molecular Carcinogenesis – Volume 1. Springer, Cham. https://doi.org/10.1007/978-3-319-53659-0_3

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