The Role of the TAM Family of Receptor Tyrosine Kinases in Neural Development and Disorders

Zhang, Jun; Qi, Xin

doi:10.4172/neuropsychiatry.1000363

Cited by 7 publications

(8 citation statements)

References 61 publications

(181 reference statements)

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“…6,9 The TAM receptor family regulates normal cellular processes and plays important roles in the nervous system development and diseases, specifically in cell proliferation/survival, cell adhesion and migration, neuronal differentiation, cell apoptosis, myelination, degeneration, and immune regulation. 6,9 However, it is not known whether TAM is involved in peripheral mechanisms of neuropathic pain. In a previous study by our group, RNA-Seq analysis of spinal nerve-ligated DRGs demonstrated a significant increase of AXL mRNA in injured L4 DRG in mice.…”

Section: Discussionmentioning

confidence: 99%

“…5,6 S-AXL binds Gas6 and acts as a ligand sink to inhibit the normal cellular functions of full-length AXL receptor. 5,6 Recent clinical studies have indicated that AXL might also be involved in pathological pain. One study showed that both s-AXL and GAS6 concentrations were increased in critical limb ischemia patients and correlated with levels of C-reactive protein, interleukin-6, tumor necrosis factor alpha, and neopterin.…”

Section: Introductionmentioning

confidence: 99%

“…4 Soluble AXL (s-AXL), which only contains the extracellular domain of the full-length receptor of AXL, exists in murine and human plasma. 5,6 S-AXL binds Gas6 and acts as a ligand sink to inhibit the normal cellular functions of full-length AXL receptor. 5,6 Recent clinical studies have indicated that AXL might also be involved in pathological pain.…”

Section: Introductionmentioning

confidence: 99%

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AXL signaling in primary sensory neurons contributes to chronic compression of dorsal root ganglion-induced neuropathic pain in rats

et al. 2020

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Low back pain is a chronic, highly prevalent, and hard-to-treat condition in the elderly. Clinical studies indicate that AXL, which belongs to the tyrosine kinase receptor subfamily, mediates pathological pain. However, it is not clear exactly how AXL regulates pain behaviors. In this study, we used a model of chronic compression of dorsal root ganglion-induced neuropathic pain to recreate clinical intervertebral foramen stenosis and related lumbocrural pain to explore whether AXL in primary sensory neurons contributes to this neuropathic pain in rats. Using double-labeling immunofluorescence, we observed that both phosphorylated AXL and AXL were localized primarily on isolectin B4-positive and calcitonin generelated peptide-positive neurons, while AXL was also localized in neurofilament-200-positive neurons. Chronic compression of dorsal root ganglion-induced pain was associated with the upregulation of AXL mRNA and protein in injured dorsal root ganglia. Repeated intrathecal administration of the AXL inhibitor, TP0903, or the AXL small interfering RNA effectively alleviated chronic compression of dorsal root ganglion-induced pain hypersensitivities. Moreover, repeated intrathecal administration of either TP0903 or AXL small interfering RNA reduced the expression of mammalian target of rapamycin in injured dorsal root ganglia, suggesting that mammalian target of rapamycin may mediate AXL's actions. These results indicate that the upregulation of dorsal root ganglion AXL may be part of a peripheral mechanism of neuropathic pain via an intracellular mammalian target of rapamycin-signaling pathway. Thus, while AXL inhibitors have so far primarily shown clinical efficacy in tumor treatment, AXL intervention could also serve as a potential target for the treatment of neuropathic pain. KeywordsAXL, mammalian target of rapamycin, chronic compression of dorsal root ganglion, neuropathic pain, dorsal root ganglion Date

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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AXL signaling in primary sensory neurons contributes to chronic compression of dorsal root ganglion-induced neuropathic pain in rats

et al. 2020

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“…RTKs regulate several cellular processes, including cellular growth, differentiation, proliferation, motility, and apoptosis in multiple organs and systems [1]. The TAM receptor subgroup has received growing attention due to the crucial role in the preservation of homeostatic balance through the modulation of immune, nervous, vascular, and reproductive functions [2–6].…”

Section: Introductionmentioning

confidence: 99%

TAM Receptor Pathways at the Crossroads of Neuroinflammation and Neurodegeneration

2019

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Increasing evidence suggests that pathogenic mechanisms underlying neurodegeneration are strongly linked with neuroinflammatory responses. Tyro3, Axl, and Mertk (TAM receptors) constitute a subgroup of the receptor tyrosine kinase family, cell surface receptors which transmit signals from the extracellular space to the cytoplasm and nucleus. TAM receptors and the corresponding ligands, Growth Arrest Specific 6 and Protein S, are expressed in different tissues, including the nervous system, playing complex roles in tissue repair, inflammation and cell survival, proliferation, and migration. In the nervous system, TAM receptor signalling modulates neurogenesis and neuronal migration, synaptic plasticity, microglial activation, phagocytosis, myelination, and peripheral nerve repair, resulting in potential interest in neuroinflammatory and neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, and Multiple Sclerosis. In Alzheimer and Parkinson diseases, a role of TAM receptors in neuronal survival and pathological protein aggregate clearance has been suggested, while in Multiple Sclerosis TAM receptors are involved in myelination and demyelination processes. To better clarify roles and pathways involving TAM receptors may have important therapeutic implications, given the fine modulation of multiple molecular processes which could be reached. In this review, we summarise the roles of TAM receptors in the central nervous system, focusing on the regulation of immune responses and microglial activities and analysing in vitro and in vivo studies regarding TAM signalling involvement in neurodegeneration.

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“…The role of TAM receptors and their ligands in cell proliferation, survival, and migration is vital in neural development and myelination (reviewed in [ 70 ]). Upon activation of Axl, Grb2 and SOS are recruited, which leads to the activation of ERK, cell migration and proliferation [ 71 ].…”

Section: Biological Functionsmentioning

confidence: 99%

The Dual Role of TAM Receptors in Autoimmune Diseases and Cancer: An Overview

Wium

Paccez

Zerbini

2018

Cells

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Receptor tyrosine kinases (RTKs) regulate cellular processes by converting signals from the extracellular environment to the cytoplasm and nucleus. Tyro3, Axl, and Mer (TAM) receptors form an RTK family that plays an intricate role in tissue maintenance, phagocytosis, and inflammation as well as cell proliferation, survival, migration, and development. Defects in TAM signaling are associated with numerous autoimmune diseases and different types of cancers. Here, we review the structure of TAM receptors, their ligands, and their biological functions. We discuss the role of TAM receptors and soluble circulating TAM receptors in the autoimmune diseases systemic lupus erythematosus (SLE) and multiple sclerosis (MS). Lastly, we discuss the effect of TAM receptor deregulation in cancer and explore the therapeutic potential of TAM receptors in the treatment of diseases.

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The Role of the TAM Family of Receptor Tyrosine Kinases in Neural Development and Disorders

Cited by 7 publications

References 61 publications

AXL signaling in primary sensory neurons contributes to chronic compression of dorsal root ganglion-induced neuropathic pain in rats

AXL signaling in primary sensory neurons contributes to chronic compression of dorsal root ganglion-induced neuropathic pain in rats

TAM Receptor Pathways at the Crossroads of Neuroinflammation and Neurodegeneration

The Dual Role of TAM Receptors in Autoimmune Diseases and Cancer: An Overview

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