Mark M R, Chen J, Hammonds R G, Sadick M, Godowsk P J
Department of Molecular Biology, Genentech, San Francisco, California 94080, USA.
J Biol Chem. 1996 Apr 19;271(16):9785-9. doi: 10.1074/jbc.271.16.9785.
Rse, Ax1, and c-Mer comprise a family of cell adhesion molecule-related tyrosine kinase receptors. Human Gas6 was recently shown to act as a ligand for both human Rse (Godowski et al., 1995) and human Ax1 (Varnum et al., 1995). Gas6 contains an NH2-terminal Gla domain followed by four epidermal growth factor-like repeats and tandem globular (G) domains. The G domains are related to those found in sex hormone-binding globulin and to those utilized by laminin and agrin for binding to the dystroglycan complex. A series of Gas6 variants were tested for their ability to bind to Rse and Ax1. The Gla domain and epidermal growth factor-like repeats were not required for receptor binding, as deletion variants of Gas6 which lacked these domains bound to the extracellular domains of both Rse and Axl. A deletion variant of Gas6 containing just the G domain region was shown to activate Rse phosphorylation. These results provide evidence that G domains can act as signaling molecules by activating transmembrane receptor tyrosine kinases. Furthermore, they provide a structural link between the activation of cell adhesion related receptors and the control of cell growth and differentiation by the G domain-containing superfamily of proteins.
Rse、Ax1和c-Mer构成了一个与细胞粘附分子相关的酪氨酸激酶受体家族。最近研究表明，人Gas6可作为人Rse（戈多夫斯基等人，1995年）和人Ax1（瓦尔纳姆等人，1995年）的配体。Gas6包含一个氨基末端Gla结构域，其后是四个表皮生长因子样重复序列和串联球状（G）结构域。G结构域与性激素结合球蛋白中的结构域以及层粘连蛋白和聚集蛋白用于结合 dystroglycan 复合物的结构域相关。测试了一系列Gas6变体与Rse和Ax1结合的能力。Gla结构域和表皮生长因子样重复序列对于受体结合并非必需，因为缺乏这些结构域的Gas6缺失变体可与Rse和Axl的细胞外结构域结合。仅包含G结构域区域的Gas6缺失变体被证明可激活Rse磷酸化。这些结果提供了证据，表明G结构域可通过激活跨膜受体酪氨酸激酶作为信号分子。此外，它们在细胞粘附相关受体的激活与含G结构域的蛋白质超家族对细胞生长和分化的控制之间提供了结构联系。
