Mitogenic Signals and Transforming Potential of Nyk, a Newly Identified Neural Cell Adhesion Molecule-Related Receptor Tyrosine Kinase

Abstract

Nyk/Mer is a recently identified receptor tyrosine kinase with neural cell adhesion molecule-like structure (two immunoglobulin G-like domains and two fibronectin III-like domains) in its extracellular region and belongs to the Ufo/Axl family of receptors. The ligand for Nyk/Mer is presently unknown, as are the signal transduction pathways mediated by this receptor. We constructed and expressed a chimeric receptor (FmsNyk) composed of the extracellular domain of the human colony-stimulating factor 1 receptor (Fms) and the transmembrane and cytoplasmic domains of human Nyk/Mer in NIH 3T3 fibroblasts in order to investigate the mitogenic signaling and biochemical properties of Nyk/Mer. Colony-stimulating factor 1 stimulation of the Fms-Nyk chimeric receptor in transfected NIH 3T3 fibroblasts leads to a transformed phenotype and generates a proliferative response in the absence of other growth factors. We show that phospholipase C␥, phosphatidylinositol 3-kinase/p70 S6 kinase, Shc, Grb2, Raf-1, and mitogen-activated protein kinase are downstream components of the Nyk/Mer signal transduction pathways. In addition, Nyk/Mer weakly activates p90 rsk , while stress-activated protein kinase, Ras GTPase-activating protein (GAP), and GAP-associated p62 and p190 proteins are not activated or tyrosine phosphorylated by Nyk/Mer. An analysis comparing the Nyk/Mer signal cascade with that of the epidermal growth factor receptor indicates substrate preferences by these two receptors. Our results provide a detailed description of the Nyk/Mer signaling pathways. Given the structural similarity between the Ufo/Axl family receptors, some of the information may also be applied to other members of this receptor tyrosine kinase family.Growth and differentiation signals are often initiated by the interactions of growth factors with specific receptors (36). For many growth factors, the receptors are tyrosine kinases. Largely on the basis of the structural motifs in the extracellular domain, the receptor tyrosine kinases can be subdivided into nine families (27). Among those, the most extensively studied are the epidermal growth factor receptor (EGFR) and platelet-derived growth factor receptor (PDGFR) families. The newest family, Ufo/Axl, is characterized by its neural cell adhesion molecule (NCAM)-related extracellular domains (i.e., two immunoglobulin G [IgG]-like domains juxtaposed with the two fibronectin III-like domains). ufo/axl was originally identified as a transforming gene derived from chronic myeloproliferative disorders (41) and chronic myelogenous leukemias (67). Ark was identified as the mouse homolog of Ufo/Axl (28, 74). As is NCAM, the NCAM domain of Ark is able to induce cell aggregation by homophilic binding, which in turn activates the kinase activity (2). In addition, recent studies have shown that soluble ligands such as Gas6 can bind and trigger the kinase activity of Ufo/Axl (88, 93). Thus, there appear to be multiple mechanisms through which this family of receptor tyrosine kinases can be activated.In the course ...

Signal Pathways in Up-regulation of Chemokines by Tyrosine Kinase MER/NYK in Prostate Cancer Cells

“…This result generally agrees with the published reports, although in some cell types, p38 activation by NYK/MER was observed (4,14,46). When the nuclear activities of some potential transcription factors were analyzed, c-Jun and c-Fos were found to increase on NYK activation.…”

“…The activation is transient and peaks around 10 minutes (Fig. 2D), consistent with the mode of activation of NYK (4).…”

“…The family consists of three members, AXL (UFO, Ark, and Tyro7), Tyro3 (SKY, Rse, Brt, Tif, Dtk, and Etk-2), and MER [Eyk, N-CAM-related kinase (NYK), and Tyro12]. The MER tyrosine kinase was first described by Graham et al (3), and our laboratory independently cloned it as NYK (4). The AXL family kinases are transcriptionally regulated by extracellular stimuli, showing significant variation in expression among different tissues and different stages of diseases (5)(6)(7).…”

TheGrowth Arrest-SpecificGene Product Gas6 Promotes the Survival of Human Oligodendrocytes via a Phosphatidylinositol 3-Kinase-Dependent Pathway

“…Analysis of the array data for receptor and kinase signaling path- (Janssen et al, 1991;Lai and Lemke, 1991;O'Bryan et al, 1991;Rescigno et al, 1991;Faust et al, 1992;Jia et al, 1992;Dai et al, 1994;Fujimoto and Yamamoto, 1994;Graham et al, 1994;Jia and Hanafusa, 1994;Lai et al, 1994;Ohashi et al, 1994;Ling and Kung, 1995). Axl and Mer expression was 11-to 12-fold above background and was among the cDNAs further studied.…”

Mer receptor tyrosine kinase promotes invasion and survival in glioblastoma multiforme

“…13 A chimeric receptor with a substitution of the MerTK extracellular domain by macrophage colony-stimulating factor receptor is able to transform NIH3T3 cells. 14 MerTK is overexpressed in several cancer types, including mantle cell lymphomas, 15 prostate cancer, 16 breast cancer 17 and melanoma. 18 In addition, MerTK knock-in mice with ectopic expression in thymocytes and lymphocytes develop T-cell lymphoblastic leukaemia/lymphoma.…”