Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Science 13 July 2001:
Vol. 293. no. 5528, pp. 306 - 311
DOI: 10.1126/science.1061663
Prev | Table of Contents | Next

Reports

Homeostatic Regulation of the Immune System by Receptor Tyrosine Kinases of the Tyro 3 Family

Qingxian Lu, Greg Lemke*

Receptor tyrosine kinases and their ligands mediate cell-cell communication and interaction in many organ systems, but have not been known to act in this capacity in the mature immune system. We now provide genetic evidence that three closely related receptor tyrosine kinases, Tyro 3, Axl, and Mer, play an essential immunoregulatory role. Mutant mice that lack these receptors develop a severe lymphoproliferative disorder accompanied by broad-spectrum autoimmunity. These phenotypes are cell nonautonomous with respect to lymphocytes and result from the hyperactivation of antigen-presenting cells in which the three receptors are normally expressed.

Molecular Neurobiology Laboratory, The Salk Institute, La Jolla, CA 92037, USA.
*   To whom correspondence should be addressed. E-mail: lemke{at}salk.edu

Read the Full Text


THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
A novel role for c-Src and STAT3 in apoptotic cell-mediated MerTK-dependent immunoregulation of dendritic cells.
Z. Yi, L. Li, G. K. Matsushima, H. S. Earp, B. Wang, and R. Tisch (2009)
Blood 114, 3191-3198
   Abstract »    Full Text »    PDF »
Functions of TAM RTKs in regulating spermatogenesis and male fertility in mice.
Y. Chen, H. Wang, N. Qi, H. Wu, W. Xiong, J. Ma, Q. Lu, and D. Han (2009)
Reproduction 138, 655-666
   Abstract »    Full Text »    PDF »
Generation and phenotypic analysis of protein S-deficient mice.
F. Saller, A. C. Brisset, S. N. Tchaikovski, M. Azevedo, R. Chrast, J. A. Fernandez, M. Schapira, T. M. Hackeng, J. H. Griffin, and A. Angelillo-Scherrer (2009)
Blood 114, 2307-2314
   Abstract »    Full Text »    PDF »
Survival and Migration of Human Dendritic Cells Are Regulated by an IFN-{alpha}-Inducible Axl/Gas6 Pathway.
S. Scutera, T. Fraone, T. Musso, P. Cappello, S. Rossi, D. Pierobon, Z. Orinska, R. Paus, S. Bulfone-Paus, and M. Giovarelli (2009)
J. Immunol. 183, 3004-3013
   Abstract »    Full Text »    PDF »
Mer tyrosine kinase (MerTK) promotes macrophage survival following exposure to oxidative stress.
A. Anwar, A. K. Keating, D. Joung, S. Sather, G. K. Kim, K. K. Sawczyn, L. Brandao, P. M. Henson, and D. K. Graham (2009)
J. Leukoc. Biol. 86, 73-79
   Abstract »    Full Text »    PDF »
PTPN22 Deficiency Cooperates with the CD45 E613R Allele to Break Tolerance on a Non-Autoimmune Background.
J. Zikherman, M. Hermiston, D. Steiner, K. Hasegawa, A. Chan, and A. Weiss (2009)
J. Immunol. 182, 4093-4106
   Abstract »    Full Text »    PDF »
MerTK regulates thymic selection of autoreactive T cells.
M. A. Wallet, R. R. Flores, Y. Wang, Z. Yi, C. J. Kroger, C. E. Mathews, H. S. Earp, G. Matsushima, B. Wang, and R. Tisch (2009)
PNAS 106, 4810-4815
   Abstract »    Full Text »    PDF »
TAM receptors and the regulation of erythropoiesis in mice.
H. Tang, S. Chen, H. Wang, H. Wu, Q. Lu, and D. Han (2009)
Haematologica 94, 326-334
   Abstract »    Full Text »    PDF »
Overexpression of Apoptotic Cell Removal Receptor MERTK in Alveolar Macrophages of Cigarette Smokers.
A. Kazeros, B.-G. Harvey, B. J. Carolan, H. Vanni, A. Krause, and R. G. Crystal (2008)
Am. J. Respir. Cell Mol. Biol. 39, 747-757
   Abstract »    Full Text »    PDF »
The scavenger receptor SR-A I/II (CD204) signals via the receptor tyrosine kinase Mertk during apoptotic cell uptake by murine macrophages.
J. C. Todt, B. Hu, and J. L. Curtis (2008)
J. Leukoc. Biol. 84, 510-518
   Abstract »    Full Text »    PDF »
Defective Mer Receptor Tyrosine Kinase Signaling in Bone Marrow Cells Promotes Apoptotic Cell Accumulation and Accelerates Atherosclerosis.
H. Ait-Oufella, V. Pouresmail, T. Simon, O. Blanc-Brude, K. Kinugawa, R. Merval, G. Offenstadt, G. Leseche, P. L. Cohen, A. Tedgui, et al. (2008)
Arterioscler Thromb Vasc Biol 28, 1429-1431
   Abstract »    Full Text »    PDF »
Gas6 Deficiency Increases Oligodendrocyte Loss and Microglial Activation in Response to Cuprizone-Induced Demyelination.
M. D. Binder, H. S. Cate, A. L. Prieto, D. Kemper, H. Butzkueven, M. M. Gresle, T. Cipriani, V. G. Jokubaitis, P. Carmeliet, and T. J. Kilpatrick (2008)
J. Neurosci. 28, 5195-5206
   Abstract »    Full Text »    PDF »
Gas6 promotes inflammation by enhancing interactions between endothelial cells, platelets, and leukocytes.
M. Tjwa, L. Bellido-Martin, Y. Lin, E. Lutgens, S. Plaisance, F. Bono, N. Delesque-Touchard, C. Herve, R. Moura, A. D. Billiau, et al. (2008)
Blood 111, 4096-4105
   Abstract »    Full Text »    PDF »
Autophosphorylation Docking Site Tyr-867 in Mer Receptor Tyrosine Kinase Allows for Dissociation of Multiple Signaling Pathways for Phagocytosis of Apoptotic Cells and Down-modulation of Lipopolysaccharide-inducible NF-{kappa}B Transcriptional Activation.
N. Tibrewal, Y. Wu, V. D'mello, R. Akakura, T. C. George, B. Varnum, and R. B. Birge (2008)
J. Biol. Chem. 283, 3618-3627
   Abstract »    Full Text »    PDF »
MerTK is required for apoptotic cell-induced T cell tolerance.
M. A. Wallet, P. Sen, R. R. Flores, Y. Wang, Z. Yi, Y. Huang, C. E. Mathews, H. S. Earp, G. Matsushima, B. Wang, et al. (2008)
J. Exp. Med. 205, 219-232
   Abstract »    Full Text »    PDF »
Gas6 and the Tyro 3 receptor tyrosine kinase subfamily regulate the phagocytic function of Sertoli cells.
W. Xiong, Y. Chen, H. Wang, H. Wang, H. Wu, Q. Lu, and D. Han (2008)
Reproduction 135, 77-87
   Abstract »    Full Text »    PDF »
Axl Mediates Vascular Remodeling Induced by Deoxycorticosterone Acetate Salt Hypertension.
V. A. Korshunov, M. Daul, M. P. Massett, and B. C. Berk (2007)
Hypertension 50, 1057-1062
   Abstract »    Full Text »    PDF »
Adhesion-Related Kinase Induction of Migration Requires Phosphatidylinositol-3-Kinase and Ras Stimulation of Rac Activity in Immortalized Gonadotropin-Releasing Hormone Neuronal Cells.
S. M. Nielsen-Preiss, M. P. Allen, M. Xu, D. A. Linseman, J. E. Pawlowski, R. J. Bouchard, B. C. Varnum, K. A. Heidenreich, and M. E. Wierman (2007)
Endocrinology 148, 2806-2814
   Abstract »    Full Text »    PDF »
The role of Tyro 3 subfamily receptors in the regulation of hemostasis and megakaryocytopoiesis.
H. Wang, S. Cnhen, Y. Chen, H. Wang, H. Wu, H. Tang, W. Xiong, J. Ma, Y. Ge, Q. Lu, et al. (2007)
Haematologica 92, 643-650
   Abstract »    Full Text »    PDF »
Macrophages and Dendritic Cells Use Different Axl/Mertk/Tyro3 Receptors in Clearance of Apoptotic Cells.
H. M. Seitz, T. D. Camenisch, G. Lemke, H. S. Earp, and G. K. Matsushima (2007)
J. Immunol. 178, 5635-5642
   Abstract »    Full Text »    PDF »
Apoptotic cells induce Mer tyrosine kinase-dependent blockade of NF-{kappa}B activation in dendritic cells.
P. Sen, M. A. Wallet, Z. Yi, Y. Huang, M. Henderson, C. E. Mathews, H. S. Earp, G. Matsushima, A. S. Baldwin Jr, and R. M. Tisch (2007)
Blood 109, 653-660
   Abstract »    Full Text »    PDF »
Tyro3 family-mediated cell entry of ebola and marburg viruses..
M. Shimojima, A. Takada, H. Ebihara, G. Neumann, K. Fujioka, T. Irimura, S. Jones, H. Feldmann, and Y. Kawaoka (2006)
J. Virol. 80, 10109-10116
   Abstract »    Full Text »    PDF »
Twist mediates suppression of inflammation by type I IFNs and Axl.
M. N. Sharif, D. Sosic, C. V. Rothlin, E. Kelly, G. Lemke, E. N. Olson, and L. B. Ivashkiv (2006)
J. Exp. Med. 203, 1891-1901
   Abstract »    Full Text »    PDF »
Axl, A Receptor Tyrosine Kinase, Mediates Flow-Induced Vascular Remodeling.
V. A. Korshunov, A. M. Mohan, M. A. Georger, and B. C. Berk (2006)
Circ. Res. 98, 1446-1452
   Abstract »    Full Text »    PDF »
Gas6/Axl Signaling Activates the Phosphatidylinositol 3-Kinase/Akt1 Survival Pathway to Protect Oligodendrocytes from Tumor Necrosis Factor{alpha}-Induced Apoptosis.
S. L. Shankar, K. O'Guin, M. Kim, B. Varnum, G. Lemke, C. F. Brosnan, and B. Shafit-Zagardo (2006)
J. Neurosci. 26, 5638-5648
   Abstract »    Full Text »    PDF »
Heterogeneous Nuclear Ribonucleoprotein P2 Is an Autoantibody Target in Mice Deficient for Mer, Axl, and Tyro3 Receptor Tyrosine Kinases.
M. Z. Radic, K. Shah, W. Zhang, Q. Lu, G. Lemke, and G. M. Hilliard (2006)
J. Immunol. 176, 68-74
   Abstract »    Full Text »    PDF »
Soluble Axl Is Generated by ADAM10-Dependent Cleavage and Associates with Gas6 in Mouse Serum.
V. Budagian, E. Bulanova, Z. Orinska, E. Duitman, K. Brandt, A. Ludwig, D. Hartmann, G. Lemke, P. Saftig, and S. Bulfone-Paus (2005)
Mol. Cell. Biol. 25, 9324-9339
   Abstract »    Full Text »    PDF »
Immunoexpression of Tyro 3 Family Receptors--Tyro 3, Axl, and Mer--and Their Ligand Gas6 in Postnatal Developing Mouse Testis.
H. Wang, Y. Chen, Y. Ge, P. Ma, Q. Ma, J. Ma, H. Wang, S. Xue, and D. Han (2005)
J. Histochem. Cytochem. 53, 1355-1364
   Abstract »    Full Text »    PDF »
Mannose-Binding Lectin-Deficient Mice Display Defective Apoptotic Cell Clearance but No Autoimmune Phenotype.
L. M. Stuart, K. Takahashi, L. Shi, J. Savill, and R. A. B. Ezekowitz (2005)
J. Immunol. 174, 3220-3226
   Abstract »    Full Text »    PDF »
Inhibition of vascular endothelial growth factor receptor 2-mediated endothelial cell activation by Axl tyrosine kinase receptor.
M. Gallicchio, S. Mitola, D. Valdembri, R. Fantozzi, B. Varnum, G. C. Avanzi, and F. Bussolino (2005)
Blood 105, 1970-1976
   Abstract »    Full Text »    PDF »
Monocytes Recruited to the Lungs of Mice during Immune Inflammation Ingest Apoptotic Cells Poorly.
J. H. Jennings, D. J. Linderman, B. Hu, J. Sonstein, and J. L. Curtis (2005)
Am. J. Respir. Cell Mol. Biol. 32, 108-117
   Abstract »    Full Text »    PDF »
Imatinib mesylate (STI-571) enhances antigen-presenting cell function and overcomes tumor-induced CD4+ T-cell tolerance.
H. Wang, F. Cheng, A. Cuenca, P. Horna, Z. Zheng, K. Bhalla, and E. M. Sotomayor (2005)
Blood 105, 1135-1143
   Abstract »    Full Text »    PDF »
Signal Pathways in Up-regulation of Chemokines by Tyrosine Kinase MER/NYK in Prostate Cancer Cells.
Y.-M. Wu, D. R. Robinson, and H.-J. Kung (2004)
Cancer Res. 64, 7311-7320
   Abstract »    Full Text »    PDF »
Progressive Glomerulonephritis and Histiocytic Sarcoma Associated with Macrophage Functional Defects in CYP1B1-Deficient Mice.
J. M. Ward, N. P. Nikolov, J. R. Tschetter, J. B. Kopp, F. J. Gonzalez, S. Kimura, and R. M. Siegel (2004)
Toxicol Pathol 32, 710-718
   Abstract »    PDF »
Hydrogen Peroxide Activates the Gas6-Axl Pathway in Vascular Smooth Muscle Cells.
A. Konishi, T. Aizawa, A. Mohan, V. A. Korshunov, and B. C. Berk (2004)
J. Biol. Chem. 279, 28766-28770
   Abstract »    Full Text »    PDF »
Nucleosomes Are Exposed at the Cell Surface in Apoptosis.
M. Radic, T. Marion, and M. Monestier (2004)
J. Immunol. 172, 6692-6700
   Abstract »    Full Text »    PDF »
Receptor tyrosine kinases and the regulation of macrophage activation.
P. H. Correll, A. C. Morrison, and M. A. Lutz (2004)
J. Leukoc. Biol. 75, 731-737
   Full Text »    PDF »
The receptor tyrosine kinase MerTK activates phospholipase C {gamma}2 during recognition of apoptotic thymocytes by murine macrophages.
J. C. Todt, B. Hu, and J. L. Curtis (2004)
J. Leukoc. Biol. 75, 705-713
   Abstract »    Full Text »    PDF »
Ligand Recognition and Homophilic Interactions in Tyro3: STRUCTURAL INSIGHTS INTO THE Axl/Tyro3 RECEPTOR TYROSINE KINASE FAMILY.
C. Heiring, B. Dahlback, and Y. A. Muller (2004)
J. Biol. Chem. 279, 6952-6958
   Abstract »    Full Text »    PDF »
Macrophage-Stimulating Protein, the Ligand for the Stem Cell-Derived Tyrosine Kinase/RON Receptor Tyrosine Kinase, Inhibits IL-12 Production by Primary Peritoneal Macrophages Stimulated with IFN-{gamma} and Lipopolysaccharide.
A. C. Morrison, C. B. Wilson, M. Ray, and P. H. Correll (2004)
J. Immunol. 172, 1825-1832
   Abstract »    Full Text »    PDF »
Impaired Clearance of Apoptotic Cells Induces the Activation of Autoreactive Anti-Sm Marginal Zone and B-1 B Cells.
Y. Qian, H. Wang, and S. H. Clarke (2004)
J. Immunol. 172, 625-635
   Abstract »    Full Text »    PDF »
Molecular Basis of Constitutive Production of Basement Membrane Components: GENE EXPRESSION PROFILES OF ENGELBRETH-HOLM-SWARM TUMOR AND F9 EMBRYONAL CARCINOMA CELLS.
S. Futaki, Y. Hayashi, M. Yamashita, K. Yagi, H. Bono, Y. Hayashizaki, Y. Okazaki, and K. Sekiguchi (2003)
J. Biol. Chem. 278, 50691-50701
   Abstract »    Full Text »    PDF »
An SH2 Domain-dependent, Phosphotyrosine-independent Interaction between Vav1 and the Mer Receptor Tyrosine Kinase: A MECHANISM FOR LOCALIZING GUANINE NUCLEOTIDE-EXCHANGE FACTOR ACTION.
N. P. Mahajan and H. S. Earp (2003)
J. Biol. Chem. 278, 42596-42603
   Abstract »    Full Text »    PDF »
Control of myeloid activity during retinal inflammation.
A. D. Dick, D. Carter, M. Robertson, C. Broderick, E. Hughes, J. V. Forrester, and J. Liversidge (2003)
J. Leukoc. Biol. 74, 161-166
   Abstract »    Full Text »    PDF »
Crystal Structure of a C-terminal Fragment of Growth Arrest-specific Protein Gas6. RECEPTOR TYROSINE KINASE ACTIVATION BY LAMININ G-LIKE DOMAINS.
T. Sasaki, P. G. Knyazev, Y. Cheburkin, W. Gohring, D. Tisi, A. Ullrich, R. Timpl, and E. Hohenester (2002)
J. Biol. Chem. 277, 44164-44170
   Abstract »    Full Text »    PDF »
Constitutive Retinal CD200 Expression Regulates Resident Microglia and Activation State of Inflammatory Cells during Experimental Autoimmune Uveoretinitis.
C. Broderick, R. M. Hoek, J. V. Forrester, J. Liversidge, J. D. Sedgwick, and A. D. Dick (2002)
Am. J. Pathol. 161, 1669-1677
   Abstract »    Full Text »    PDF »
Delayed Apoptotic Cell Clearance and Lupus-like Autoimmunity in Mice Lacking the c-mer Membrane Tyrosine Kinase.
P. L. Cohen, R. Caricchio, V. Abraham, T. D. Camenisch, J. C. Jennette, R. A.S. Roubey, H. S. Earp, G. Matsushima, and E. A. Reap (2002)
J. Exp. Med. 196, 135-140
   Abstract »    Full Text »    PDF »
Blebs and Apoptotic Bodies Are B Cell Autoantigens.
B. A. Cocca, A. M. Cline, and M. Z. Radic (2002)
J. Immunol. 169, 159-166
   Abstract »    Full Text »    PDF »
Mer Receptor Tyrosine Kinase Signaling. PREVENTION OF APOPTOSIS AND ALTERATION OF CYTOSKELETAL ARCHITECTURE WITHOUT STIMULATION OR PROLIFERATION.
K. L. Guttridge, J. C. Luft, T. L. Dawson, E. Kozlowska, N. P. Mahajan, B. Varnum, and H. S. Earp (2002)
J. Biol. Chem. 277, 24057-24066
   Abstract »    Full Text »    PDF »


To Advertise     Find Products

Science. ISSN 0036-8075 (print), 1095-9203 (online)