TAM receptor tyrosine kinases: biologic functions, signaling, and potential therapeutic targeting in human cancer.

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 downstream 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 overexpressed 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.

[1]  C. Brosnan,et al.  Gas6/Axl Signaling Activates the Phosphatidylinositol 3-Kinase/Akt1 Survival Pathway to Protect Oligodendrocytes from Tumor Necrosis Factorα-Induced Apoptosis , 2006, The Journal of Neuroscience.

[2]  G. Lemke,et al.  Structure, expression, and activity of Tyro 3, a neural adhesion-related receptor tyrosine kinase. , 1994, Oncogene.

[3]  B. Berk,et al.  Axl, A Receptor Tyrosine Kinase, Mediates Flow-Induced Vascular Remodeling , 2006, Circulation research.

[4]  P. Carmeliet,et al.  Deficiency or inhibition of Gas6 causes platelet dysfunction and protects mice against thrombosis , 2001, Nature Medicine.

[5]  A. Goddard,et al.  rse, a novel receptor-type tyrosine kinase with homology to Axl/Ufo, is expressed at high levels in the brain. , 1994, The Journal of biological chemistry.

[6]  E. Liu,et al.  Differential activation of the Ras/extracellular-signal-regulated protein kinase pathway is responsible for the biological consequences induced by the Axl receptor tyrosine kinase , 1996, Molecular and cellular biology.

[7]  M. Lavail,et al.  Correction of the retinal dystrophy phenotype of the RCS rat by viral gene transfer of Mertk , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[8]  D. Hanahan,et al.  The Hallmarks of Cancer , 2000, Cell.

[9]  H. Drexler,et al.  Differential expression of the ufo/axl oncogene in human leukemia-lymphoma cell lines. , 1996, Leukemia.

[10]  W. Gerald,et al.  Endogenous human microRNAs that suppress breast cancer metastasis , 2008, Nature.

[11]  David A. Chesnutt,et al.  rek, a Gene Expressed in Retina and Brain, Encodes a Receptor Tyrosine Kinase of the Axl/Tyro3 Family* , 1996, The Journal of Biological Chemistry.

[12]  L. Castello,et al.  Gas6 induces proliferation in prostate carcinoma cell lines expressing the Axl receptor , 2005, Journal of cellular physiology.

[13]  M. Ehinger,et al.  Mantle cell lymphomas express a distinct genetic signature affecting lymphocyte trafficking and growth regulation as compared with subpopulations of normal human B cells. , 2002, Cancer research.

[14]  E. Attar,et al.  GAS6 Induces Axl-mediated Chemotaxis of Vascular Smooth Muscle Cells* , 1998, The Journal of Biological Chemistry.

[15]  B. Dahlbäck,et al.  Gas6 and protein S , 2006, The FEBS journal.

[16]  P. Stein,et al.  The mer receptor tyrosine kinase: expression and function suggest a role in innate immunity , 2003, European journal of immunology.

[17]  L. Mayo,et al.  Cell Type-specific Expression of the IκB Kinases Determines the Significance of Phosphatidylinositol 3-Kinase/Akt Signaling to NF-κB Activation* , 2003, Journal of Biological Chemistry.

[18]  T. Yamamoto,et al.  brt, a mouse gene encoding a novel receptor-type protein-tyrosine kinase, is preferentially expressed in the brain. , 1994, Oncogene.

[19]  R. Hansen,et al.  MCF-10A-NeoST: a new cell system for studying cell-ECM and cell-cell interactions in breast cancer. , 2001, Clinical cancer research : an official journal of the American Association for Cancer Research.

[20]  H. Arita,et al.  Vascular Smooth Muscle Cell-derived, Gla-containing Growth-potentiating Factor for Ca-mobilizing Growth Factors (*) , 1995, The Journal of Biological Chemistry.

[21]  J. Downing,et al.  Classification, subtype discovery, and prediction of outcome in pediatric acute lymphoblastic leukemia by gene expression profiling. , 2002, Cancer cell.

[22]  J. Yokota,et al.  Biological properties and gene expression associated with metastatic potential of human osteosarcoma , 2004, Clinical & Experimental Metastasis.

[23]  A. Tall,et al.  Cholesterol-induced Apoptotic Macrophages Elicit an Inflammatory Response in Phagocytes, Which Is Partially Attenuated by the Mer Receptor* , 2006, Journal of Biological Chemistry.

[24]  E. Kandel,et al.  Novel Mechanism for Gonadotropin-Releasing Hormone Neuronal Migration Involving Gas6/Ark Signaling to p38 Mitogen-Activated Protein Kinase , 2002, Molecular and Cellular Biology.

[25]  R. Scott,et al.  Phagocytosis and clearance of apoptotic cells is mediated by MER , 2001, Nature.

[26]  S. Jacobson,et al.  Retinal dystrophy due to paternal isodisomy for chromosome 1 or chromosome 2, with homoallelism for mutations in RPE65 or MERTK, respectively. , 2002, American journal of human genetics.

[27]  D. Brat,et al.  The Journal of Clinical Endocrinology & Metabolism Printed in U.S.A. Copyright © 2001 by The Endocrine Society Novel Patterns of Gene Expression in Pituitary Adenomas Identified by Complementary Deoxyribonucleic Acid Microarrays and Quantitative , 2000 .

[28]  B. Dahlbäck,et al.  The Ran binding protein RanBPM interacts with Axl and Sky receptor tyrosine kinases. , 2005, The international journal of biochemistry & cell biology.

[29]  M. Obin,et al.  Role of Gas6/Axl signaling in lens epithelial cell proliferation and survival. , 2004, Experimental eye research.

[30]  R. Spritz,et al.  The human TYRO3 gene and pseudogene are located in chromosome 15q14-q25. , 1993, Gene.

[31]  D. Huhn,et al.  Expression of axl, a transforming receptor tyrosine kinase, in normal and malignant hematopoiesis. , 1994, Blood.

[32]  B. Koller,et al.  A novel receptor tyrosine kinase, Mer, inhibits TNF-alpha production and lipopolysaccharide-induced endotoxic shock. , 1999, Journal of immunology.

[33]  W. Lee,et al.  Identification and regulation of receptor tyrosine kinases Rse and Mer and their ligand Gas6 in testicular somatic cells. , 2000, Journal of andrology.

[34]  M. Cavet,et al.  Gas6 inhibits apoptosis in vascular smooth muscle: role of Axl kinase and Akt. , 2004, Journal of molecular and cellular cardiology.

[35]  A. Kraus,et al.  Axl receptor tyrosine kinase expression in human lung cancer cell lines correlates with cellular adhesion. , 2001, European journal of cancer.

[36]  D. Robinson,et al.  The protein tyrosine kinase family of the human genome , 2000, Oncogene.

[37]  C. Chi,et al.  Clinical significance of AXL kinase family in gastric cancer. , 2002, Anticancer research.

[38]  E. Ruaro,et al.  Requirement of phosphatidylinositol 3-kinase-dependent pathway and Src for Gas6-Axl mitogenic and survival activities in NIH 3T3 fibroblasts , 1997, Molecular and cellular biology.

[39]  H. Weier,et al.  Assignment1 of protooncogene MERTK (a.k.a. c-mer) to human chromosome 2q14.1 by in situ hybridization , 1999, Cytogenetic and Genome Research.

[40]  Michael L. Bittner,et al.  cDNA microarrays detect activation of a myogenic transcription program by the PAX3-FKHR fusion oncogene. , 1999 .

[41]  J. Weber,et al.  Expression of the receptor protein‐tyrosine kinases Tyro‐3, Axl, and Mer in the developing rat central nervous system , 2000, The Journal of comparative neurology.

[42]  B. Hjelle,et al.  Transforming genes in chronic myelogenous leukemia. , 1988, Proceedings of the National Academy of Sciences of the United States of America.

[43]  M. K. Meintzer,et al.  Growth arrest-specific gene 6 (Gas6)/adhesion related kinase (Ark) signaling promotes gonadotropin-releasing hormone neuronal survival via extracellular signal-regulated kinase (ERK) and Akt. , 1999, Molecular endocrinology.

[44]  B. Chung,et al.  Expression of the proto-oncogene Axl in renal cell carcinoma. , 2003, DNA and cell biology.

[45]  P. Godowski,et al.  Identification of Gas6 as a ligand for Mer, a neural cell adhesion molecule related receptor tyrosine kinase implicated in cellular transformation , 1997, Oncogene.

[46]  B. Berk,et al.  Increased expression of Axl tyrosine kinase after vascular injury and regulation by G protein-coupled receptor agonists in rats. , 1998, Circulation research.

[47]  J. Smyth,et al.  Altered ErbB receptor signaling and gene expression in cisplatin-resistant ovarian cancer. , 2005, Cancer research.

[48]  L. Meltesen,et al.  Lymphoblastic leukemia/lymphoma in mice overexpressing the Mer (MerTK) receptor tyrosine kinase , 2006, Oncogene.

[49]  P. Reuland,et al.  A phase I study of neuroblastoma with the anti-ganglioside GD2 antibody 14.G2a , 2005, Cancer Immunology, Immunotherapy.

[50]  H. Kung,et al.  Identification of the Major Autophosphorylation Sites of Nyk/Mer, an NCAM-related Receptor Tyrosine Kinase* , 1996, The Journal of Biological Chemistry.

[51]  D. Beier,et al.  Isolation of a receptor tyrosine kinase (DTK) from embryonic stem cells: structure, genetic mapping and analysis of expression. , 1994, Growth factors.

[52]  R. Timpl,et al.  Crystal Structure of a C-terminal Fragment of Growth Arrest-specific Protein Gas6 , 2002, The Journal of Biological Chemistry.

[53]  P. Lewis,et al.  Identification of a novel receptor tyrosine kinase expressed in acute myeloid leukemic blasts. , 1995, Leukemia & lymphoma.

[54]  B. Dahlbäck,et al.  C1‐TEN is a negative regulator of the Akt/PKB signal transduction pathway and inhibits cell survival, proliferation, and migration , 2005, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[55]  Kozo Nakamura,et al.  Mechanism of Stimulation of Osteoclastic Bone Resorption through Gas6/Tyro 3, a Receptor Tyrosine Kinase Signaling, in Mouse Osteoclasts* , 2001, The Journal of Biological Chemistry.

[56]  L. Biesecker,et al.  Identification of four murine cDNAs encoding putative protein kinases from primitive embryonic stem cells differentiated in vitro. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[57]  M. Kubo,et al.  SOCS1/JAB is a negative regulator of LPS-induced macrophage activation. , 2002, Immunity.

[58]  H. Garewal,et al.  A novel tyrosine kinase switch is a mechanism of imatinib resistance in gastrointestinal stromal tumors , 2007, Oncogene.

[59]  W Y Lui,et al.  tie-1 protein tyrosine kinase: a novel independent prognostic marker for gastric cancer. , 1999, Clinical cancer research : an official journal of the American Association for Cancer Research.

[60]  Balazs Györffy,et al.  A Web-based data warehouse on gene expression in human malignant melanoma. , 2007, The Journal of investigative dermatology.

[61]  H. Yamane,et al.  Axl receptor tyrosine kinase stimulated by the vitamin K-dependent protein encoded by growth-arrest-specific gene 6 , 1995, Nature.

[62]  B. Coiffier,et al.  European phase II study of rituximab (chimeric anti-CD20 monoclonal antibody) for patients with newly diagnosed mantle-cell lymphoma and previously treated mantle-cell lymphoma, immunocytoma, and small B-cell lymphocytic lymphoma. , 2000, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[63]  Y. Sasaguri,et al.  A product of growth arrest‐specific gene 6 modulates scavenger receptor expression in human vascular smooth muscle cells , 1999, FEBS letters.

[64]  B. Dahlbäck,et al.  Signalling and functional diversity within the Axl subfamily of receptor tyrosine kinases. , 2006, Cytokine & growth factor reviews.

[65]  M. Schwartz,et al.  Protein kinase C regulates alpha v beta 5-dependent cytoskeletal associations and focal adhesion kinase phosphorylation , 1996, The Journal of cell biology.

[66]  R. Koski,et al.  The Transforming Receptor Tyrosine Kinase, Axl, Is Post-translationally Regulated by Proteolytic Cleavage (*) , 1995, The Journal of Biological Chemistry.

[67]  Biesecker Lg,et al.  Identification of alternative exons, including a novel exon, in the tyrosine kinase receptor gene Etk2/tyro3 that explain differences in 5' cDNA sequences. , 1995 .

[68]  Jinquan Luo,et al.  A novel site contributing to growth-arrest-specific gene 6 binding to its receptors as revealed by a human monoclonal antibody. , 2005, The Biochemical journal.

[69]  P. Carmeliet,et al.  Role of Gas6 receptors in platelet signaling during thrombus stabilization and implications for antithrombotic therapy. , 2005, The Journal of clinical investigation.

[70]  M. Lavail,et al.  Mutation of the receptor tyrosine kinase gene Mertk in the retinal dystrophic RCS rat. , 2000, Human molecular genetics.

[71]  Pamela F. Jones,et al.  The anticoagulation factor protein S and its relative, Gas6, are ligands for the Tyro 3/Axl family of receptor tyrosine kinases , 1995, Cell.

[72]  D. Albert,et al.  Expression of the Receptor Tyrosine Kinase Axl Promotes Ocular Melanoma Cell Survival , 2004, Cancer Research.

[73]  B. Dahlbäck,et al.  Ligand Recognition and Homophilic Interactions in Tyro3 , 2004, Journal of Biological Chemistry.

[74]  M. Essig,et al.  Dominant-negative inhibition of the Axl receptor tyrosine kinase suppresses brain tumor cell growth and invasion and prolongs survival. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[75]  J. Curtis,et al.  Resident murine alveolar and peritoneal macrophages differ in adhesion of apoptotic thymocytes. , 2004, American journal of respiratory cell and molecular biology.

[76]  Chemotaxis of Vascular Smooth Muscle Cells by Lysyl Oxidase , 2000 .

[77]  M. Bihoreau,et al.  Homozygous Deletion in the Coding Sequence of the c-mer Gene in RCS Rats Unravels General Mechanisms of Physiological Cell Adhesion and Apoptosis , 2000, Neurobiology of Disease.

[78]  M. Hung,et al.  Akt is required for Axl-Gas6 signaling to protect cells from E1A-mediated apoptosis , 2002, Oncogene.

[79]  H. Hanafusa,et al.  The proto-oncogene of v-eyk (v-ryk) is a novel receptor-type protein tyrosine kinase with extracellular Ig/GN-III domains. , 1994, The Journal of biological chemistry.

[80]  James L Mohler,et al.  Activated tyrosine kinase Ack1 promotes prostate tumorigenesis: role of Ack1 in polyubiquitination of tumor suppressor Wwox. , 2005, Cancer research.

[81]  Qingxian Lu,et al.  Homeostatic Regulation of the Immune System by Receptor Tyrosine Kinases of the Tyro 3 Family , 2001, Science.

[82]  E. Ruaro,et al.  Gas6-mediated survival in NIH3T3 cells activates stress signalling cascade and is independent of Ras , 1999, Oncogene.

[83]  F. Meric,et al.  Expression profile of tyrosine kinases in breast cancer. , 2002, Clinical cancer research : an official journal of the American Association for Cancer Research.

[84]  Paloma Valverde,et al.  Effects of Gas6 and hydrogen peroxide in Axl ubiquitination and downregulation. , 2005, Biochemical and biophysical research communications.

[85]  R. Birge,et al.  A role for Mer tyrosine kinase in alphavbeta5 integrin-mediated phagocytosis of apoptotic cells. , 2005, Journal of cell science.

[86]  Connie C. S. Wong,et al.  The proximal cis-acting elements Sp1, Sp3 and E2F regulate mouse mer gene transcription in Sertoli cells. , 2002, European journal of biochemistry.

[87]  Qingxian Lu,et al.  Macrophage regulation by Tyro 3 family receptors. , 2003, Current opinion in immunology.

[88]  R. Verardo,et al.  Gas6 anti-apoptotic signaling requires NF-kappa B activation. , 2001, The Journal of biological chemistry.

[89]  C. Paweletz,et al.  Serum-derived protein S binds to phosphatidylserine and stimulates the phagocytosis of apoptotic cells , 2003, Nature Immunology.

[90]  G. Gill,et al.  Receptor tyrosine kinases , 1992, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[91]  L. Biesecker,et al.  Identification of alternative exons, including a novel exon, in the tyrosine kinase receptor gene Etk2/tyro3 that explain differences in 5' cDNA sequences. , 1995, Oncogene.

[92]  K. Ohashi,et al.  Autophosphorylation activity and association with Src family kinase of Sky receptor tyrosine kinase. , 1995, Biochemical and Biophysical Research Communications - BBRC.

[93]  R. Paus,et al.  A promiscuous liaison between IL‐15 receptor and Axl receptor tyrosine kinase in cell death control , 2005, The EMBO journal.

[94]  W. Dai,et al.  Transforming activity of receptor tyrosine kinase tyro3 is mediated, at least in part, by the PI3 kinase-signaling pathway. , 2000, Blood.

[95]  T. Tamaya,et al.  Coexpression of growth arrest-specific gene 6 and receptor tyrosine kinases Axl and Sky in human uterine endometrial cancers. , 2003, Annals of oncology : official journal of the European Society for Medical Oncology.

[96]  A. Schulz,et al.  The murine ufo receptor: molecular cloning, chromosomal localization and in situ expression analysis. , 1992, Oncogene.

[97]  H. Namba,et al.  Expression Profile of Receptor-Type Protein Tyrosine Kinase Genes in the Human Thyroid , 1998 .

[98]  C. Basilico,et al.  A putative receptor tyrosine kinase with unique structural topology. , 1991, Oncogene.

[99]  B. Varnum,et al.  Mer Receptor Tyrosine Kinase Signaling , 2002, The Journal of Biological Chemistry.

[100]  A. Schulz,et al.  The genomic structure of the human UFO receptor. , 1993, Oncogene.

[101]  R. Birge,et al.  A role for Mer tyrosine kinase in αvβ5 integrin-mediated phagocytosis of apoptotic cells , 2005, Journal of Cell Science.

[102]  Kenji Nakanishi,et al.  SOCS-1 participates in negative regulation of LPS responses. , 2002, Immunity.

[103]  J. Charles Jennette,et al.  Delayed Apoptotic Cell Clearance and Lupus-like Autoimmunity in Mice Lacking the c-mer Membrane Tyrosine Kinase , 2002, The Journal of experimental medicine.

[104]  H. Hanafusa,et al.  Identification of the Product of Growth Arrest-specific Gene 6 as a Common Ligand for Axl, Sky, and Mer Receptor Tyrosine Kinases* , 1996, The Journal of Biological Chemistry.

[105]  S. Jacobson,et al.  Mutations in MERTK, the human orthologue of the RCS rat retinal dystrophy gene, cause retinitis pigmentosa , 2000, Nature Genetics.

[106]  G. Lemke,et al.  Macrophages and Dendritic Cells Use Different Axl/Mertk/Tyro3 Receptors in Clearance of Apoptotic Cells1 , 2007, The Journal of Immunology.

[107]  H. Snodgrass,et al.  Cloning and Mrna Expression Analysis of a Novel Human Protooncogene, C-merr , 2022 .

[108]  H. Hanafusa,et al.  Biological Effects of c-Mer Receptor Tyrosine Kinase in Hematopoietic Cells Depend on the Grb2 Binding Site in the Receptor and Activation of NF-κB , 1999, Molecular and Cellular Biology.

[109]  Qingxian Lu,et al.  TAM receptor function in the retinal pigment epithelium , 2006, Molecular and Cellular Neuroscience.

[110]  H. Varmus,et al.  Mouse Mammary Tumors Express Elevated Levels of RNA Encoding the Murine Homolog of SKY, a Putative Receptor Tyrosine Kinase (*) , 1995, The Journal of Biological Chemistry.

[111]  R. Kandpal,et al.  A receptor tyrosine kinase, UFO/Axl, and other genes isolated by a modified differential display PCR are overexpressed in metastatic prostatic carcinoma cell line DU145. , 1999, Cancer detection and prevention.

[112]  J. Curtis,et al.  The receptor tyrosine kinase MerTK activates phospholipase C γ2 during recognition of apoptotic thymocytes by murine macrophages , 2004, Journal of leukocyte biology.

[113]  K. Ohashi,et al.  Cell Adhesion to Phosphatidylserine Mediated by a Product of Growth Arrest-specific Gene 6* , 1997, The Journal of Biological Chemistry.

[114]  M. Cammer,et al.  The Growth Arrest-Specific Gene Product Gas6 Promotes the Survival of Human Oligodendrocytes via a Phosphatidylinositol 3-Kinase-Dependent Pathway , 2003, The Journal of Neuroscience.

[115]  Toshikazu Nakamura,et al.  Identification of Gas6, a putative ligand for Sky and Axl receptor tyrosine kinases, as a novel neurotrophic factor for hippocampal neurons , 2002, Journal of neuroscience research.

[116]  H. Snodgrass,et al.  Ectopic Expression of the Proto-oncogene Mer in Pediatric T-Cell Acute Lymphoblastic Leukemia , 2006, Clinical Cancer Research.

[117]  T. Nakano,et al.  Stimulation of Sky Receptor Tyrosine Kinase by the Product of Growth Arrest-specific Gene 6(*) , 1995, The Journal of Biological Chemistry.

[118]  B. Dahlbäck,et al.  Interaction of Axl receptor tyrosine kinase with C1-TEN, a novel C1 domain-containing protein with homology to tensin. , 2002, Biochemical and biophysical research communications.

[119]  S. Yamashita,et al.  Expression of the Axl receptor tyrosine kinase in human thyroid carcinoma. , 1999, Thyroid : official journal of the American Thyroid Association.

[120]  J. Curtis,et al.  Activation of Protein Kinase C βII by the Stereo-specific Phosphatidylserine Receptor Is Required for Phagocytosis of Apoptotic Thymocytes by Resident Murine Tissue Macrophages* , 2002, The Journal of Biological Chemistry.

[121]  R. Tisch,et al.  Apoptotic cells induce Mer tyrosine kinase-dependent blockade of NF-kappaB activation in dendritic cells. , 2007, Blood.

[122]  K. Heidenreich,et al.  Adhesion-related kinase induction of migration requires phosphatidylinositol-3-kinase and ras stimulation of rac activity in immortalized gonadotropin-releasing hormone neuronal cells. , 2007, Endocrinology.

[123]  E. Liu,et al.  Determinants for transformation induced by the Axl receptor tyrosine kinase , 1998, Oncogene.

[124]  B. Mayer,et al.  A novel oncogene, v-ryk, encoding a truncated receptor tyrosine kinase is transduced into the RPL30 virus without loss of viral sequences , 1992, Journal of virology.

[125]  J. D. Vos,et al.  Identifying intercellular signaling genes expressed in malignant plasma cells by using complementary DNA arrays. , 2001, Blood.

[126]  H. Tsuchiya,et al.  Effect of timing of pulmonary metastases identification on prognosis of patients with osteosarcoma: the Japanese Musculoskeletal Oncology Group study. , 2002, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[127]  N. Mahajan,et al.  An SH2 Domain-dependent, Phosphotyrosine-independent Interaction between Vav1 and the Mer Receptor Tyrosine Kinase , 2003, Journal of Biological Chemistry.

[128]  H. Snodgrass,et al.  Cloning and developmental expression analysis of the murine c-mer tyrosine kinase. , 1995, Oncogene.

[129]  Analysis of the murine Dtk gene identifies conservation of genomic structure within a new receptor tyrosine kinase subfamily. , 1996, Genomics.

[130]  R. Herrmann,et al.  Axl expression is associated with adverse prognosis and with expression of Bcl-2 and CD34 in de novo acute myeloid leukemia (AML): results from a multicenter trial of the Swiss Group for Clinical Cancer Research (SAKK) , 1999, Leukemia.

[131]  D. Bodine,et al.  The Dtk receptor tyrosine kinase, which binds protein S, is expressed during hematopoiesis. , 1996, Experimental hematology.

[132]  A. Bird,et al.  Clinical characterisation of a family with retinal dystrophy caused by mutation in the Mertk gene , 2006, British Journal of Ophthalmology.

[133]  S. Chuang,et al.  Sulfasalazine suppresses drug resistance and invasiveness of lung adenocarcinoma cells expressing AXL. , 2007, Cancer research.

[134]  B. Varnum,et al.  A soluble form of the Mer receptor tyrosine kinase inhibits macrophage clearance of apoptotic cells and platelet aggregation. , 2007, Blood.

[135]  W. Birchmeier,et al.  Met, metastasis, motility and more , 2003, Nature Reviews Molecular Cell Biology.

[136]  T. Nakano,et al.  Promotion of the uptake of PS liposomes and apoptotic cells by a product of growth arrest-specific gene, gas6. , 2000, Journal of biochemistry.

[137]  H. Kung,et al.  Mitogenic signals and transforming potential of Nyk, a newly identified neural cell adhesion molecule-related receptor tyrosine kinase , 1995, Molecular and cellular biology.

[138]  Y. Chu,et al.  Expression of axl in lung adenocarcinoma and correlation with tumor progression. , 2005, Neoplasia.

[139]  B. Coiffier,et al.  Treatment of mantle-cell lymphoma with Rituximab (chimeric monoclonal anti-CD20 antibody): analysis of factors associated with response. , 2000, Annals of oncology : official journal of the European Society for Medical Oncology.

[140]  E. Dreher,et al.  Estrogen dependent expression of the receptor tyrosine kinase axl in normal and malignant human breast. , 2001, Annals of oncology : official journal of the European Society for Medical Oncology.

[141]  M. Nakashima,et al.  Expression of receptor-type tyrosine kinase, Axl, and its ligand, Gas6, in pediatric thyroid carcinomas around chernobyl. , 2002, Thyroid : official journal of the American Thyroid Association.

[142]  C. Basilico,et al.  Cleavage and release of a soluble form of the receptor tyrosine kinase ARK in vitro and in vivo , 1996, Journal of cellular physiology.

[143]  S. Goff,et al.  Signaling through the ARK tyrosine kinase receptor protects from apoptosis in the absence of growth stimulation , 1997, Oncogene.

[144]  G. Lemke,et al.  An extended family of protein-tyrosine kinase genes differentially expressed in the vertebrate nervous system , 1991, Neuron.

[145]  B. Dahlbäck,et al.  Vitamin K-dependent Gas6 activates ERK kinase and stimulates growth of cardiac fibroblasts. , 2004, Biochemical and biophysical research communications.

[146]  Stephen T. C. Wong,et al.  Multiple roles for the receptor tyrosine kinase axl in tumor formation. , 2005, Cancer research.

[147]  M. Blostein,et al.  Intracellular signaling pathways involved in Gas6-Axl-mediated survival of endothelial cells. , 2004, American journal of physiology. Heart and circulatory physiology.

[148]  H. Kung,et al.  Signal Pathways in Up-regulation of Chemokines by Tyrosine Kinase MER/NYK in Prostate Cancer Cells , 2004, Cancer Research.

[149]  K. Nishida,et al.  Screening of the MERTK gene for mutations in Japanese patients with autosomal recessive retinitis pigmentosa. , 2006, Molecular vision.

[150]  Greg Lemke,et al.  Twist mediates suppression of inflammation by type I IFNs and Axl , 2006, The Journal of experimental medicine.

[151]  R. Verardo,et al.  Gas6 Anti-apoptotic Signaling Requires NF-κB Activation* , 2001, The Journal of Biological Chemistry.

[152]  M. Mark,et al.  Characterization of Gas6, a Member of the Superfamily of G Domain-containing Proteins, as a Ligand for Rse and Axl (*) , 1996, The Journal of Biological Chemistry.

[153]  K. Novak.  Receptor tyrosine kinases: Getting on TRK , 2004, Nature Reviews Cancer.

[154]  R. Timpl,et al.  Structural basis for Gas6–Axl signalling , 2006, The EMBO journal.

[155]  K. Kuma,et al.  Cloning of the cDNA for a novel receptor tyrosine kinase, Sky, predominantly expressed in brain. , 1994, Oncogene.

[156]  L. Mayo,et al.  Cell type-specific expression of the IkappaB kinases determines the significance of phosphatidylinositol 3-kinase/Akt signaling to NF-kappa B activation. , 2004, The Journal of biological chemistry.

[157]  Daishu Han,et al.  The role of Tyro 3 subfamily receptors in the regulation of hemostasis and megakaryocytopoiesis. , 2007, Haematologica.

[158]  Qingxian Lu,et al.  Natural killer cell differentiation driven by Tyro3 receptor tyrosine kinases , 2006, Nature Immunology.

[159]  J. Sanes,et al.  Synaptic adhesion molecules. , 2003, Current opinion in cell biology.

[160]  C. Basilico,et al.  The receptor tyrosine kinase ARK mediates cell aggregation by homophilic binding , 1995, Molecular and cellular biology.

[161]  P. Godowski,et al.  Reevaluation of the roles of protein S and gas6 as ligands for the receptor tyrosine kinase Rse/Tyro 3 , 1995, Cell.

[162]  R. Espinosa,et al.  axl, a transforming gene isolated from primary human myeloid leukemia cells, encodes a novel receptor tyrosine kinase , 1991, Molecular and cellular biology.

[163]  M. Lavail,et al.  An RCS-like retinal dystrophy phenotype in mer knockout mice. , 2003, Investigative ophthalmology & visual science.

[164]  H. Pan,et al.  Molecular cloning of a novel receptor tyrosine kinase, tif, highly expressed in human ovary and testis. , 1994, Oncogene.

[165]  A. Schulz,et al.  A novel putative tyrosine kinase receptor with oncogenic potential. , 1991, Oncogene.

[166]  Z. Li.  Growth arrest-specific genes and their research progress , 2009 .

[167]  T. Tamaya,et al.  Coexpression of Gas6/Axl in Human Ovarian Cancers , 2004, Oncology.

[168]  A. Ullrich,et al.  Intracellular signaling of the Ufo/Axl receptor tyrosine kinase is mediated mainly by a multi-substrate docking-site , 1997, Oncogene.

[169]  J. Schlessinger,et al.  Cell Signaling by Receptor Tyrosine Kinases , 2000, Cell.

[170]  Peter M. G. Munro,et al.  Long-term preservation of retinal function in the RCS rat model of retinitis pigmentosa following lentivirus-mediated gene therapy , 2005, Gene Therapy.

[171]  M. Herlyn,et al.  Protein kinases in normal and transformed melanocytes , 1994, Melanoma research.

[172]  D. Hartmann,et al.  Associates with Gas6 in Mouse Serum Adam10-dependent Cleavage and Soluble Axl Is Generated by Supplemental Material , 2005 .

[173]  S. Goff,et al.  Tyro-3 family receptors are essential regulators of mammalian spermatogenesis , 1999, Nature.

[174]  J. Weber,et al.  Gas6, a ligand for the receptor protein-tyrosine kinase Tyro-3, is widely expressed in the central nervous system 1 Published on the World Wide Web on 2 December 1998. 1 , 1999, Brain Research.

[175]  E. Liu,et al.  Receptor tyrosine kinases expressed in metastatic colon cancer , 1995, International journal of cancer.

[176]  B. Dahlbäck,et al.  beta-Hydroxyasparagine in domains homologous to the epidermal growth factor precursor in vitamin K-dependent protein S. , 1987, Proceedings of the National Academy of Sciences of the United States of America.

[177]  B. Varnum,et al.  GAS6 Mediates Adhesion of Cells Expressing the Receptor Tyrosine Kinase Axl* , 1997, The Journal of Biological Chemistry.

[178]  M. Schrappe,et al.  A phase I study of human/mouse chimeric antiganglioside GD2 antibody ch14.18 in patients with neuroblastoma. , 1995, European journal of cancer.

[179]  S. Tsai,et al.  Parallel hybridization analysis of multiple protein kinase genes: identification of gene expression patterns characteristic of human hepatocellular carcinoma. , 1998, Genomics.

[180]  P. Sieving,et al.  MERTK arginine-844-cysteine in a patient with severe rod-cone dystrophy: loss of mutant protein function in transfected cells. , 2004, Investigative ophthalmology & visual science.

[181]  H. Varmus,et al.  Overexpression of the Sky receptor tyrosine kinase at the cell surface or in the cytoplasm results in ligand-independent activation. , 1995, Oncogene.