Axl Phosphorylates Elmo Scaffold Proteins To Promote Rac Activation and Cell Invasion

Abu-Thuraia, Afnan; Gauthier, Rosemarie; Chidiac, Rony; Fukui, Yoshihiro; Screaton, Robert A.; Gratton, Jean‐Philippe; Côté, Jean

doi:10.1128/mcb.00764-14

Cited by 62 publications

(58 citation statements)

References 61 publications

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“…In preclinical studies, genetic inactivation of AXL is sufficient to decrease the migratory, invasive and metastatic potential of tumor cells [15,17,28,41,42,51,62,63,68,80,81]. While there are multiple mechanisms by which AXL signaling promotes metastasis, the majority of studies have focused on defining the role of GAS6/AXL signaling in the early stages of metastasis.…”

Section: Mechanisms Of Axl-mediated Tumor Progression and Metastasismentioning

confidence: 99%

The Receptor Tyrosine Kinase AXL in Cancer Progression

Rankin

Giaccia

2016

Cancers

128

102

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The AXL receptor tyrosine kinase (AXL) has emerged as a promising therapeutic target for cancer therapy. Recent studies have revealed a central role of AXL signaling in tumor proliferation, survival, stem cell phenotype, metastasis, and resistance to cancer therapy. Moreover, AXL is expressed within cellular components of the tumor microenvironment where AXL signaling contributes to the immunosuppressive and protumorigenic phenotypes. A variety of AXL inhibitors have been developed and are efficacious in preclinical studies. These agents offer new opportunities for therapeutic intervention in the prevention and treatment of advanced disease. Here we review the literature that has illuminated the cellular and molecular mechanisms by which AXL signaling promotes tumor progression and we will discuss the therapeutic potential of AXL inhibition for cancer therapy.

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Section: Mechanisms Of Axl-mediated Tumor Progression and Metastasismentioning

confidence: 99%

The Receptor Tyrosine Kinase AXL in Cancer Progression

Rankin

Giaccia

2016

Cancers

128

102

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“…AXL activation and downstream signaling propagation results in enhanced cell motility and invasion by increasing filopodia formation and cell-to-cell interactions (27). This phenotype is mechanistically explained, at least in part, by the AXL-mediated phosphorylation of engulfment and cell motility scaffold protein that, in turn, promotes Rac-mediated cytoskeleton changes, resulting in increased cancer cell migration (28). Accordingly, this is reversed by both AXL and Rac inhibition (29).…”

Section: Introductionmentioning

confidence: 99%

Molecular Pathways: AXL, a Membrane Receptor Mediator of Resistance to Therapy

Scaltriti

Elkabets

Baselga

2016

Clinical Cancer Research

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AXL is a tyrosine kinase membrane receptor that signals via PI3K, MAPK, and protein kinase C (PKC), among other pathways. AXL has oncogenic potential and interacts with other membrane receptors, depending on their relative abundance and availability. The increased expression of AXL in cancer is often the result of pharmacologic selective pressure to a number of chemotherapies and targeted therapies and acts as a mechanism of acquired drug resistance. This resistance phenotype, frequently accompanied by epithelial-to-mesenchymal transition, can be reversed by AXL inhibition. In tumors with high levels of EGFR, including lung, head and neck, and triple-negative breast cancer, AXL dimerizes with this receptor and initiates signaling that circumvents the antitumor effects of anti-EGFR therapies. Likewise, AXL overexpression and dimerization with EGFR can overcome PI3K inhibition by activating the phospholipase C-γ-PKC cascade that, in turn, sustains mTORC1 activity. The causative role of AXL in inducing drug resistance is underscored by the fact that the suppression of AXL restores sensitivity to these agents. Hence, these observations indicate that AXL is selectively expressed in tumor cells refractory to therapy and that cotargeting AXL in this setting would potentially overcome drug resistance. The use of AXL inhibitors should be considered in the clinic.

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“…16,17 Axl can also activate Rac1, leading to cytoskeletal reorganization and a more mesenchymal-like phenotype, characterized by increased migration and invasion. 18 …”

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confidence: 99%

Axl Receptor Axis: A New Therapeutic Target in Lung Cancer

Levin

Brekken

Byers

et al. 2016

Journal of Thoracic Oncology

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The Axl receptor tyrosine kinase belongs to the TAM (Tyro3, Axl, Mer) family of proteins and is upregulated in multiple types of cancers, including non-small cell lung cancer. In normal tissues, TAM receptor tyrosine kinases contribute to immune regulation. In cancer, Axl expression is associated with poor outcomes and is controlled through various transcriptional and epigenetic mechanisms. Preclinical studies have shown that Axl is involved in cancer cell migration, growth, survival and resistance to chemotherapy through activation of multiple downstream signaling pathways, such as Ras/MAPK, PI3K and Rac1. Axl is also expressed on endothelial cells and plays a role in angiogenesis. In preclinical models, Axl inhibition decreases cancer growth and impedes lung cancer metastases. Small molecule Axl inhibitors have been developed and are currently being used as monotherapy or in combination with cytotoxic chemotherapy or anti-EGFR therapy in early clinical trials. Here, we review Axl structure, functions, regulation, and preclinical and clinical studies in lung cancer.

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Axl Phosphorylates Elmo Scaffold Proteins To Promote Rac Activation and Cell Invasion

Cited by 62 publications

References 61 publications

The Receptor Tyrosine Kinase AXL in Cancer Progression

The Receptor Tyrosine Kinase AXL in Cancer Progression

Molecular Pathways: AXL, a Membrane Receptor Mediator of Resistance to Therapy

Axl Receptor Axis: A New Therapeutic Target in Lung Cancer

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