GAS6 Enhances Repair Following Cuprizone-Induced Demyelination

Growth arrest-specific protein 6 (gas6) activities are mediated through the Tyro3, Axl, and Mer family of receptor tyrosine kinases. Gas6 is expressed and secreted by a wide variety of cell types, including cells of the central nervous system (CNS). In this study, we tested the hypothesis that administration of recombinant human Gas6 (rhGas6) protein into the CNS improves recovery following cuprizone withdrawal. After a 4-week cuprizone diet, cuprizone was removed and PBS or rhGas6 (400 ng/ml, 4 µg/ml and 40 µg/ml) was delivered by osmotic mini-pump into the corpus callosum of C57Bl6 mice for 14 days. Nine of 11 (82%) PBS-treated mice had abundant lipid-associated debris in the corpus callosum by Oil-Red-O staining while only 4 of 19 (21%) mice treated with rhGas6 had low Oil-Red-O positive droplets. In rhGas6-treated mice, SMI32-positive axonal spheroids and APP-positive deposits were reduced in number relative to PBS-treated mice. Compared to PBS, rhGas6 enhanced remyelination as revealed by MBP immunostaining and electron microscopy. The rhGas6-treated mice had more oligodendrocytes expressing Olig1 in the cytoplasm, indicative of oligodendrocyte progenitor cell maturation. Relative to PBS-treated mice, rhGas6-treated mice had fewer activated microglia in the corpus callosum by Iba1 immunostaining. The data show that rhGas6 treatment resulted in more efficient repair following cuprizone-induced injury

AXL receptor kinase is a mediator of YAP-dependent oncogenic functions in hepatocellular carcinoma

10.1038/onc.2010.504Oncogene30101229-1240ONCN

The E3 ligase Cbl-b and TAM receptors regulate cancer metastasis via natural killer cells

Tumour metastasis is the primary cause of mortality in cancer patients and remains the key challenge for cancer therapy. New therapeutic approaches to block inhibitory pathways of the immune system have renewed hopes for the utility of such therapies2. Here we show that genetic deletion of the E3 ubiquitin ligase Cbl-b (casitas B-lineage lymphoma-b) or targeted inactivation of its E3 ligase activity licenses natural killer (NK) cells to spontaneously reject metastatic tumours. The TAM tyrosine kinase receptors Tyro3, Axl and Mer (also known as Mertk) were identified as ubiquitylation substrates for Cbl-b. Treatment of wild-type NK cells with a newly developed small molecule TAM kinase inhibitor conferred therapeutic potential, efficiently enhancing anti-metastatic NK cell activity in vivo. Oral or intraperitoneal administration using this TAM inhibitor markedly reduced murine mammary cancer and melanoma metastases dependent on NK cells. We further report that the anticoagulant warfarin exerts anti-metastatic activity in mice via Cbl-b/TAM receptors in NK cells, providing a molecular explanation for a 50-year-old puzzle in cancer biology3. This novel TAM/Cbl-b inhibitory pathway shows that it might be possible to develop a a 'pill' that awakens the innate immune system to kill cancer metastases. © 2014 Macmillan Publishers Limited.Fil: Paolino, Magdalena. Institute Of Molecular Biotechnology, Vienna; AustriaFil: Choidas, Axel. Lead Discovery Center GmbH; AlemaniaFil: Wallner, Stephanie. Medizinische Universitat Innsbruck; AustriaFil: Pranjic, Blanka. Institute Of Molecular Biotechnology, Vienna; AustriaFil: Uribesalgo, Iris. Institute Of Molecular Biotechnology, Vienna; AustriaFil: Loeser, Stefanie. Institute Of Molecular Biotechnology, Vienna; AustriaFil: Jamieson, Amanda M.. University Brown; Estados UnidosFil: Langdon, Wallace Y.. University of Western Australia; AustraliaFil: Ikeda, Fumiyo. Institute Of Molecular Biotechnology, Vienna; AustriaFil: Fededa, Juan Pablo. Institute Of Molecular Biotechnology, Vienna; Austria. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; ArgentinaFil: Cronin, Shane J.. Institute Of Molecular Biotechnology, Vienna; AustriaFil: Nitsch, Roberto. Institute Of Molecular Biotechnology, Vienna; AustriaFil: Schultz-Fademrecht, Carsten. Lead Discovery Center GmbH; AlemaniaFil: Eickhoff, Jan. Lead Discovery Center GmbH; AlemaniaFil: Menninger, Sascha. Lead Discovery Center GmbH; AlemaniaFil: Unger, Anke. Lead Discovery Center GmbH; AlemaniaFil: Torka, Robert. Institute for Biochemistry Max-Planck; AlemaniaFil: Gruber, Thomas. Medizinische Universitat Innsbruck; AustriaFil: Hinterleitner, Reinhard. Medizinische Universitat Innsbruck; AustriaFil: Baier, Gottfried. Medizinische Universitat Innsbruck; AustriaFil: Wolf, Dominik. University Hospital Bonn; Alemania. Medical University Innsbruck; AustriaFil: Ullrich, Axel. Institute for Biochemistry Max-Planck; AlemaniaFil: Klebl, Bert M.. Lead Discovery Center GmbH; AlemaniaFil: Penninger, Josef M.. Institute Of Molecular Biotechnology, Vienna; Austri