TY - JOUR
T1 - Up-regulation of soluble Axl and Mer receptor tyrosine kinases negatively correlates with Gas6 in established multiple sclerosis lesions
AU - Weinger, Jason G.
AU - Omari, Kakuri M.
AU - Marsden, Kurt
AU - Raine, Cedric S.
AU - Shafit-Zagardo, Bridget
N1 - Funding Information:
Supported by the National Multiple Sclerosis Society research grants RG3020 (to B.S.Z.) and RG4046 (to B.S.Z.), National Institutes of Health grant NINDS1R21NS061128 (to B.S.Z.), a, National Institutes of Health Training Program in Cellular and Molecular Biology and Genetics grant NIGMS GM07491 (to J.G.W.), National Multiple Sclerosis Society grant RG1001-K-11 (to C.S.R.), National Institutes of Health grant NS 08952 (to C.S.R.), and National Multiple Sclerosis Society fellowship FG1422-A-1 (to K.M.O.). C.S.R. is Wollowick Family Professor of MS research.
PY - 2009/7
Y1 - 2009/7
N2 - Multiple sclerosis is a disease that is characterized by inflammation, demyelination, and axonal damage; it ultimately forms gliotic scars and lesions that severely compromise the function of the central nervous system. Evidence has shown previously that altered growth factor receptor signaling contributes to lesion formation, impedes recovery, and plays a role in disease progression. Growth arrest-specific protein 6 (Gas6), the ligand for the TAM receptor tyrosine kinase family, consisting of Tyro3, Axl, and Mer, is important for cell growth, survival, and clearance of debris. In this study, we show that levels of membrane-bound Mer (205 kd), soluble Mer (⌈150 kd), and soluble Axl (80 kd) were all significantly elevated in homogenates from established multiple sclerosis lesions comprised of both chronic active and chronic silent lesions. Whereas in normal tissue Gas6 positively correlated with soluble Axl and Mer, there was a negative correlation between Gas6 and soluble Axl and Mer in established multiple sclerosis lesions. In addition, increased levels of soluble Axl and Mer were associated with increased levels of mature ADAM17, mature ADAM10, and Furin, proteins that are associated with Axl and Mer solubilization. Soluble Axl and Mer are both known to act as decoy receptors and block Gas6 binding to membrane-bound receptors. These data suggest that in multiple sclerosis lesions, dysregulation of protective Gas6 receptor signaling may prolong lesion activity.
AB - Multiple sclerosis is a disease that is characterized by inflammation, demyelination, and axonal damage; it ultimately forms gliotic scars and lesions that severely compromise the function of the central nervous system. Evidence has shown previously that altered growth factor receptor signaling contributes to lesion formation, impedes recovery, and plays a role in disease progression. Growth arrest-specific protein 6 (Gas6), the ligand for the TAM receptor tyrosine kinase family, consisting of Tyro3, Axl, and Mer, is important for cell growth, survival, and clearance of debris. In this study, we show that levels of membrane-bound Mer (205 kd), soluble Mer (⌈150 kd), and soluble Axl (80 kd) were all significantly elevated in homogenates from established multiple sclerosis lesions comprised of both chronic active and chronic silent lesions. Whereas in normal tissue Gas6 positively correlated with soluble Axl and Mer, there was a negative correlation between Gas6 and soluble Axl and Mer in established multiple sclerosis lesions. In addition, increased levels of soluble Axl and Mer were associated with increased levels of mature ADAM17, mature ADAM10, and Furin, proteins that are associated with Axl and Mer solubilization. Soluble Axl and Mer are both known to act as decoy receptors and block Gas6 binding to membrane-bound receptors. These data suggest that in multiple sclerosis lesions, dysregulation of protective Gas6 receptor signaling may prolong lesion activity.
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U2 - 10.2353/ajpath.2009.080807
DO - 10.2353/ajpath.2009.080807
M3 - Article
C2 - 19541935
AN - SCOPUS:67649935007
SN - 0002-9440
VL - 175
SP - 283
EP - 293
JO - American Journal of Pathology
JF - American Journal of Pathology
IS - 1
ER -