Gas6/Axl Signaling Activates the Phosphatidylinositol 3-Kinase/Akt1 Survival Pathway to Protect Oligodendrocytes from Tumor Necrosis Factorα-Induced Apoptosis

Shankar, Sai Latha; O’Guin, Kathleen; Kim, Mimi; Varnum, Brian; Lemke, Greg; Brosnan, Celia F.; Shafit‐Zagardo, Bridget

doi:10.1523/jneurosci.5063-05.2006

Cited by 93 publications

(91 citation statements)

References 38 publications

(50 reference statements)

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“…Additional studies suggest that Gas6/Axl receptor signaling activates PI3K-dependent survival pathways in numerous other cells types, including lens epithelial cells, vascular smooth muscle cells, GnRH neurons, and oligodendrocytes (Allen et al, 1999;Melaragno et al, 2004;Shankar et al, 2003;Valverde et al, 2004). Further study in oligodendrocytes from WT, Axl−/−, and Tyro-3−/− mice suggest that Axl is required for Gas6-PI3K-Akt-mediated survival (Shankar et al, 2006).…”

Section: Mer Signaling-much Of the Evidence Delineating Mer Signalingmentioning

confidence: 93%

TAM Receptor Tyrosine Kinases: Biologic Functions, Signaling, and Potential Therapeutic Targeting in Human Cancer

Linger¹,

Keating²,

Earp

et al. 2008

Advances in Cancer Research

620

688

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Tyro-3, Axl, and Mer constitute the TAM family of receptor tyrosine kinases (RTKs) characterized by a conserved sequence within the kinase domain and adhesion molecule-like extracellular domains. This small family of RTKs regulates an intriguing mix of processes, including cell proliferation/survival, cell adhesion and migration, blood clot stabilization, and regulation of inflammatory cytokine release. Genetic or experimental alteration of TAM receptor function can contribute to a number of disease states, including coagulopathy, autoimmune disease, retinitis pigmentosa, and cancer. In this chapter, we first provide a comprehensive review of the structure, regulation, biologic functions, and down-stream signaling pathways of these receptors. In addition, we discuss recent evidence which suggests a role for TAM receptors in oncogenic mechanisms as family members are over-expressed in a spectrum of human cancers and have prognostic significance in some. Possible strategies for targeted inhibition of the TAM family in the treatment of human cancer are described. Further research will be necessary to evaluate the full clinical implications of TAM family expression and activation in cancer.

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Section: Mer Signaling-much Of the Evidence Delineating Mer Signalingmentioning

confidence: 93%

TAM Receptor Tyrosine Kinases: Biologic Functions, Signaling, and Potential Therapeutic Targeting in Human Cancer

Linger¹,

Keating²,

Earp

et al. 2008

Advances in Cancer Research

620

688

View full text Add to dashboard Cite

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Section: Box 1 | Tam Receptor Signalling In Other Tissues and Organsmentioning

confidence: 99%

“…TAM receptors are also implicated in the regulation of osteoclast function 100,101 , in the control of oligodendrocyte cell survival 102,103 , and in the infection of dendritic cells and other cells by Ebola and Marburg viruses 104,105 . In many of these instances, the primary downstream TAM signalling pathway appears to be the phosphoinositide 3-kinase-AKT pathway 95,97,99,102,103 , rather than the Janus kinase-STAT (signal transducer and activator of transcription) pathway that is highlighted in this Review.Because knockout of each of the TAM genes still produced viable and fertile mice, and because the Tyro3 and Mer genes are linked in the mouse genome, it was possible to generate knockout mice that were deficient for all three TAM receptors 20 . Remarkably, even these triple knockout mice were found to be viable at birth, and to be superficially normal for the first several weeks thereafter.…”

mentioning

confidence: 99%

Immunobiology of the TAM receptors

2008

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Recent studies have revealed that the TAM receptor protein tyrosine kinases -TYRO3, AXL and MER -have pivotal roles in innate immunity. They inhibit inflammation in dendritic cells and macrophages, promote the phagocytosis of apoptotic cells and membranous organelles, and stimulate the maturation of natural killer cells. Each of these phenomena may depend on a cooperative interaction between TAM receptor and cytokine receptor signalling systems. Although its importance was previously unrecognized, TAM signalling promises to have an increasingly prominent role in studies of innate immune regulation.Receptor protein tyrosine kinases (PTKs) are cell-surface transmembrane receptors that contain a regulated PTK activity within their cytoplasmic domains. They function as sensors for extracellular ligands, the binding of which triggers receptor dimerization and activation of the receptor's kinase. This leads to the recruitment, phosphorylation and activation of multiple downstream signalling proteins, which ultimately change the physiology of cells. Although there are only 58 receptor PTK genes in the human genome 1 (see the human kinome website), the signal transduction cascades initiated by receptor PTK activation control diverse cellular processes -from cell differentiation to cell death. Well-known receptor PTK subfamilies include the ERBB receptors, which have essential roles in cardiac and neural development and the progression of some forms of breast cancer 2 ; and the ephrin receptors, which are required for tissue morphogenesis and the patterning of neuronal connections in the developing brain 3 .The focus of this Review, the TAM group, was among the last receptor PTK subfamilies to be identified, and the biological roles of its three members -TYRO3, AXL and MERremained uncharacterized for several years. Largely through the analysis of engineered lossof-function mutants in mice, these roles have become increasingly apparent. They reflect a specific requirement for TAM signalling in settings in which fully differentiated cells, tissues and organs must be maintained in the face of continuous challenge, turnover and renewal. In humans, ongoing homeostatic regulation of this sort must be carried out, frequently on a daily basis, for decades. Although an essential role for TAM regulation of tissue homeostasis is evident in the adult nervous, reproductive and vascular systems, it is in In this Review, we highlight the central roles that TAM signalling has in the intrinsic inhibition of the inflammatory response to pathogens by dendritic cells (DCs) and macrophages; during phagocytosis of apoptotic cells by these same cells; and in the maturation and killing activity of natural killer (NK) cells. We also discuss how, in many or all of these settings, TAM receptors depend on and interact with cytokine receptors. TAM receptors and ligandsThe three TAM receptors, TYRO3, AXL and MER, were identified as a distinct receptor PTK subfamily in 1991 (REFS 4,5 ). Subsequent cloning of full-length cDNAs by multiple labo...

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“…TAM receptor signaling has been shown to regulate vascular smooth muscle homeostasis (Korshunov et al, 2006(Korshunov et al, , 2007, platelet function, thrombus stabilization (Angelillo-Scherrer et al, 2001;Gould et al, 2005) and erythropoiesis (AngelilloScherrer et al, 2008). TAM receptors are also implicated in the control of oligodendrocyte cell survival (Shankar et al, 2006) and in the regulation of osteoclast function (Katagiri et al, 2001). Recent studies in knockout mice have revealed that TAM receptors play pivotal roles in innate immunity (Lemke and Rothlin, 2008).…”

Section: Introductionmentioning

confidence: 99%

“…TAM inhibits inflammation in macrophages and dendritic cells (Sharif et al, 2006;Rothlin et al, 2007), promotes the phagocytosis of apoptotic cells (Lu et al, 1999;Prasad et al, 2006) and stimulates the differentiation of natural killer cells (Caraux et al, 2006). In many of these instances, the primary downstream TAM signaling pathway appears to be PI3K/AKT pathway (Angelillo-Scherrer et al, 2001;Keating et al, 2006;Shankar et al, 2006); however, the Janus kinase-STAT pathway is essential for TAM-mediated immune responses (Rothlin et al, 2007). In addition, cooperative interaction between TAM receptor and cytokine receptor signaling network is required for many TAM-regulated biological functions (Budagian et al, 2005b;Rothlin et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

Axl as a potential therapeutic target in cancer: role of Axl in tumor growth, metastasis and angiogenesis

Tan³

et al. 2009

Oncogene

254

271

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Dysregulation of Axl and its ligand growth arrest-specific 6 is implicated in the pathogenesis of several human cancers. In this study, we have used RNAi and monoclonal antibodies to assess further the oncogenic potential of Axl. Here we show that Axl knockdown reduces growth of lung and breast cancer xenograft tumors. Inhibition of Axl expression attenuates breast cancer cell migration and inhibits metastasis to the lung in an orthotopic model, providing the first in vivo evidence that links Axl directly to cancer metastasis. Axl knockdown in endothelial cells impaired tube formation and this effect was additive with anti-vascular endothelial growth factor (VEGF). Further analysis demonstrated that Axl regulates endothelial cell functions by modulation of signaling through angiopoietin/Tie2 and Dickkopf (DKK3) pathways. We have developed and characterized Axl monoclonal antibodies that attenuate non-small cell lung carcinoma xenograft growth by downregulation of receptor expression, reducing tumor cell proliferation and inducing apoptosis. Our data demonstrate that Axl plays multiple roles in tumorigenesis and that therapeutic antibodies against Axl may block Axl functions not only in malignant tumor cells but also in the tumor stroma. The additive effect of Axl inhibition with anti-VEGF suggests that blocking Axl function could be an effective approach for enhancing antiangiogenic therapy.

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Gas6/Axl Signaling Activates the Phosphatidylinositol 3-Kinase/Akt1 Survival Pathway to Protect Oligodendrocytes from Tumor Necrosis Factorα-Induced Apoptosis

Cited by 93 publications

References 38 publications

TAM Receptor Tyrosine Kinases: Biologic Functions, Signaling, and Potential Therapeutic Targeting in Human Cancer

TAM Receptor Tyrosine Kinases: Biologic Functions, Signaling, and Potential Therapeutic Targeting in Human Cancer

Immunobiology of the TAM receptors

Axl as a potential therapeutic target in cancer: role of Axl in tumor growth, metastasis and angiogenesis

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