Ling L, Kung H J
Department of Molecular Biology and Microbiology, Case Western Reserve University, School of Medicine, Cleveland, Ohio 44106-4960, USA.
Mol Cell Biol. 1995 Dec;15(12):6582-92. doi: 10.1128/MCB.15.12.6582.
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 (Fms-Nyk) 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 gamma, 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 p90rsk, 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.
Nyk/Mer是一种最近鉴定出的受体酪氨酸激酶，其胞外区域具有神经细胞黏附分子样结构（两个免疫球蛋白G样结构域和两个纤连蛋白III样结构域），属于Ufo/Axl受体家族。目前尚不清楚Nyk/Mer的配体以及该受体介导的信号转导途径。我们构建并在NIH 3T3成纤维细胞中表达了一种嵌合受体（Fms-Nyk），它由人集落刺激因子1受体（Fms）的胞外结构域与人Nyk/Mer的跨膜和胞质结构域组成，以研究Nyk/Mer的促有丝分裂信号和生化特性。在转染的NIH 3T3成纤维细胞中，集落刺激因子1刺激Fms-Nyk嵌合受体可导致转化表型，并在没有其他生长因子的情况下产生增殖反应。我们表明，磷脂酶Cγ、磷脂酰肌醇3激酶/p70 S6激酶、Shc、Grb2、Raf-1和丝裂原活化蛋白激酶是Nyk/Mer信号转导途径的下游成分。此外，Nyk/Mer可微弱激活p90rsk，而应激激活蛋白激酶、Ras GTP酶激活蛋白（GAP）以及与GAP相关的p62和p190蛋白不会被Nyk/Mer激活或酪氨酸磷酸化。一项比较Nyk/Mer信号级联与表皮生长因子受体信号级联的分析表明了这两种受体对底物的偏好。我们的结果详细描述了Nyk/Mer信号转导途径。鉴于Ufo/Axl家族受体之间的结构相似性，其中一些信息可能也适用于该受体酪氨酸激酶家族的其他成员。
