Function of Axl receptor tyrosine kinase in non-small cell lung cancer

Abstract

Axl receptor tyrosine kinase (hereafter Axl) is a member of the tyrosine-protein kinase receptor Tyro3, Axl and proto-oncogene tyrosine-protein kinase Mer family of receptor tyrosine kinases, possessing multiple different functions in normal cells. Axl is overexpressed and activated in numerous different human cancer types, triggering several signaling pathways and enhancing tumor progression. The present review assesses previous studies on the function of Axl in non-small cell lung cancer (NSCLC). Axl is overexpressed in the tumor tissues of a number of patients with NSCLC and is associated with poorer clinical outcomes; it promotes NSCLC tumor growth, invasion/metastasis, drug resistance and the epithelial-mesenchymal transition, thus providing a survival advantage to tumor cells. Therefore, Axl may be a promising target in NSCLC treatment.

Keywords: Axl receptor tyrosine kinase; drug resistance; epithelial-mesenchymal transition; invasion; metastasis; non-small cell lung cancer.

Figure 1.

Schematic representation of the Axl signaling pathway. Activation of Axl by Gas6 binding results in the autophosphorylation of several tyrosine residues in the intracellular domain, including Y-779, Y-821 and Y-866, which provide docking sites for signaling proteins and consequently result in the activation of the PI3K/Akt pathway, RAS/ERK pathway, STAT3 pathway, NF-κB pathway, PLCγ-Ca²⁺/PKC pathway and Elmo2-Rac pathway, promoting tumor proliferation, survival and migration. The question mark represents the tyrosine sites responsible for JAK and Elmo2 activation remain unknown. Gas6, growth arrest-specific 6; PI3K, phosphoinositide 3-kinase; Akt, protein kinase B; ERK, extracellular signal-regulated kinase; STAT3, signal transducer and activator of transcription 3; NF-κB, nuclear factor-κB; PLCγ, phosphoinositide phospholipase Cγ; PKC, protein kinase C; Elmo2, engulfment and cell motility 2; JAK, Janus kinase.