Clinical Neurobiology, Institute of Translational and Stratified Medicine, Plymouth University Peninsula Schools of Medicine and Dentistry, Plymouth, UK.
Department of Histopathology, Derriford Hospital, Plymouth, UK.
Oncogene. 2014 Jan 16;33(3):336-46. doi: 10.1038/onc.2012.587. Epub 2013 Jan 14.
TAM family receptor tyrosine kinases comprising Tyro3 (Sky), Axl, and Mer are overexpressed in some cancers, correlate with multidrug resistance and contribute to tumourigenesis by regulating invasion, angiogenesis, cell survival and tumour growth. Mutations in the gene coding for a tumour suppressor merlin cause development of multiple tumours of the nervous system such as schwannomas, meningiomas and ependymomas occurring spontaneously or as part of a hereditary disease neurofibromatosis type 2. The benign character of merlin-deficient tumours makes them less responsive to chemotherapy. We previously showed that, amongst other growth factor receptors, TAM family receptors (Tyro3, Axl and Mer) are significantly overexpressed in schwannoma tissues. As Axl is negatively regulated by merlin and positively regulated by E3 ubiquitin ligase CRL4DCAF1, previously shown to be a key regulator in schwannoma growth we hypothesized that Axl is a good target to study in merlin-deficient tumours. Moreover, Axl positively regulates the oncogene Yes-associated protein, which is known to be under merlin regulation in schwannoma and is involved in increased proliferation of merlin-deficient meningioma and mesothelioma. Here, we demonstrated strong overexpression and activation of Axl receptor as well as its ligand Gas6 in human schwannoma primary cells compared to normal Schwann cells. We show that Gas6 is mitogenic and increases schwannoma cell-matrix adhesion and survival acting via Axl in schwannoma cells. Stimulation of the Gas6/Axl signalling pathway recruits Src, focal adhesion kinase (FAK) and NFκB. We showed that NFκB mediates Gas6/Axl-mediated overexpression of survivin, cyclin D1 and FAK, leading to enhanced survival, cell-matrix adhesion and proliferation of schwannoma. We conclude that Axl/FAK/Src/NFκB pathway is relevant in merlin-deficient tumours and is a potential therapeutic target for schwannoma and other merlin-deficient tumours.
TAM 家族受体酪氨酸激酶包括 Tyro3（Sky）、Axl 和 Mer，在一些癌症中过度表达，与多药耐药性相关，并通过调节侵袭、血管生成、细胞存活和肿瘤生长促进肿瘤发生。编码肿瘤抑制因子 merlin 的基因突变导致多种神经系统肿瘤的发生，如神经鞘瘤、脑膜瘤和室管膜瘤，这些肿瘤自发发生或作为遗传性疾病神经纤维瘤病 2 的一部分发生。 Merlin 缺陷型肿瘤的良性特征使其对化疗的反应性降低。我们之前表明，在其他生长因子受体中，TAM 家族受体（Tyro3、Axl 和 Mer）在神经鞘瘤组织中显著过表达。由于 Axl 受 merlin 负调控，受 E3 泛素连接酶 CRL4DCAF1 正调控，先前被证明是神经鞘瘤生长的关键调节剂，我们假设 Axl 是 merlin 缺陷型肿瘤中研究的一个很好的靶点。此外，Axl 正向调节癌基因 Yes 相关蛋白，已知该蛋白在神经鞘瘤中受 merlin 调节，并且参与 merlin 缺陷型脑膜瘤和间皮瘤的增殖增加。在这里，我们证明了与正常 Schwann 细胞相比，人神经鞘瘤原代细胞中 Axl 受体及其配体 Gas6 的过表达和激活。我们表明 Gas6 具有有丝分裂原活性，通过 Axl 在 schwannoma 细胞中增加 schwannoma 细胞-基质粘附和存活。Gas6/Axl 信号通路的刺激招募Src、粘着斑激酶（FAK）和 NFκB。我们表明 NFκB 介导 Gas6/Axl 介导的 survivin、cyclin D1 和 FAK 的过表达，导致 schwannoma 的存活、细胞-基质粘附和增殖增强。我们得出结论，Axl/FAK/Src/NFκB 通路在 merlin 缺陷型肿瘤中具有相关性，是 schwannoma 和其他 merlin 缺陷型肿瘤的潜在治疗靶点。
