Akt is required for Axl-Gas6 signaling to protect cells from E1A-mediated apoptosis

Lee, Wei Ping; Wen, Yong; Varnum, Brian; Hung, Mien‐Chie

doi:10.1038/sj.onc.1205066

Cited by 77 publications

(74 citation statements)

References 40 publications

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“…Furthermore, addition of Axl-ext acellular domain to block the binding of Gas6 to Axl clearly abrogated the inhibitory effect of Gas6 25) . Consistent with a study by Lee et al 32) , the phosphorylation of Akt was downregulated by Pi and rhGas6 abrogated the decrease. Wortmannin, a specific PI3K inhibitor, abolished the rhGas6-induced phosphorylation of Akt and further eliminated the inhibitory effect of Gas6 on Pi-induced apoptosis and calcification 33) .…”

Section: Downregulation Of Gas6-mediated Survival Pathway Plays a Pivsupporting

confidence: 80%

Mechanism of Pi-induced Vascular Calcification - Regulation of Growth Arrest-Specific Gene 6 (Gas6)-Mediated Survival Pathway

Son

Akishita

Iijima

et al. 2008

JAT

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Vascular calcification is clinically important in the development of cardiovascular disease. It has been suggested that apoptosis is one of the processes regulating calcification in vascular smooth muscle cells (VSMC). In this review, we discuss the role of apoptosis in inorganic phosphate (Pi)-induced calcification, focusing on regulation of the survival pathway mediated by growth arrest-specific gene 6 (Gas6). Further, we mention the beneficial effect of statins mediated by inhibition of apoptosis which is accompanied by restoration of the Gas6-mediated survival pathway. These findings indicate that Gas6 is a novel target of statins' effects to prevent vascular calcification.

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Section: Downregulation Of Gas6-mediated Survival Pathway Plays a Pivsupporting

confidence: 80%

Mechanism of Pi-induced Vascular Calcification - Regulation of Growth Arrest-Specific Gene 6 (Gas6)-Mediated Survival Pathway

Son

Akishita

Iijima

et al. 2008

JAT

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“…Axl is a 140-kDa protein, activated either with growth-arrest-specific gene 6 (Gas6) or homophilic interactions and activates different signaling molecules like phosphatidylinositol 3-kinase, Akt, Src, extracellular signal-regulated kinase and nuclear factor kappaB (Goruppi et al, 1997;Lee et al, 2002;Vajkoczy et al, 2006). Overexpression of Axl can transform fibroblasts even in the absence of a ligand (Burchert et al, 1998).…”

Section: Introductionmentioning

confidence: 99%

Regulation of Axl receptor tyrosine kinase expression by miR-34a and miR-199a/b in solid cancer

et al. 2011

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Axl is a receptor that induces proliferation, migration and invasion in cancer. In this study, we show that specific microRNAs (miRNAs) target the 3 0 -UTR of Axl. Luciferase-reporter assays with wild-type and deleted miR-34 and miR-199a/b seed sequences of Axl 3 0 -UTR confirmed the specificity of targeting. An inverse correlation between Axl protein and miR-34a expression in a panel of non-small cell lung cancer (NSCLC), colorectal cancer (CRC) and breast cancer (BRC) cell lines was observed, while miR-199a/b expression was completely suppressed. Pre-miR transfection inhibited in vitro migration and invasion and, in vivo, reduced the number of distant lung-or liver-metastases in a chorion-allantoicmembrane (CAM) assay. Moreover, methylation-specific PCR on bisulfite-converted DNA obtained from the cell lines showed that the miR-34a promoter methylation status was inversely correlated with its expression, and that miR-199a/b promoter regions were methylated in all cells tested. In a panel of NSCLC tissues (n ¼ 44), miR34a and miR-199a/b were found to be downregulated and significantly co-expressed. A lower expression of all three miRs was significantly associated with squamous histotypes, and, in a preliminary series, NSCLC patients with miR-34a upregulation showed a positive association towards a longer survival. These results indicate that Axl receptor expression can be regulated by miR-34a and miR-199a/b, which are suppressed by promoter methylation in solid cancer cells.

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“…One pathway involves classical PI3K stimulation of Akt and S6K (Goruppi et al, 1997). Gas6 also stimulates phosphorylation of Bad, a target of Akt commonly associated with prosurvival signaling (Goruppi et al, 1999;Lee et al, 2002). Other survival pathways downstream of Gas6-Axl signaling via PI3K/Akt include phosphorylation of NFκB, increased expression of antiapoptotic proteins such as Bcl-2 and Bcl-x L , and inhibition of proapoptotic proteins such as caspase 3 (Demarchi et al, 2001;Hasanbasic et al, 2004).…”

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

confidence: 99%

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

Linger¹,

Keating²,

Earp

et al. 2008

Advances in Cancer Research

616

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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Akt is required for Axl-Gas6 signaling to protect cells from E1A-mediated apoptosis

Cited by 77 publications

References 40 publications

Mechanism of Pi-induced Vascular Calcification - Regulation of Growth Arrest-Specific Gene 6 (Gas6)-Mediated Survival Pathway

Mechanism of Pi-induced Vascular Calcification - Regulation of Growth Arrest-Specific Gene 6 (Gas6)-Mediated Survival Pathway

Regulation of Axl receptor tyrosine kinase expression by miR-34a and miR-199a/b in solid cancer

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

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