van Weering D H, Medema J P, van Puijenbroek A, Burgering B M, Baas P D, Bos J L
Graduate School of Developmental Biology, Laboratory for Physiological Chemistry, Utrecht University, The Netherlands.
Oncogene. 1995 Dec 7;11(11):2207-14.
Ret is a receptor tyrosine kinase predominantly expressed in tissue derived from the neuroectoderm and is involved in multiple endocrine neoplasia type 2A and 2B, familiar medullary thyroid carcinoma, and Hirschsprung's disease. The ligand for the receptor is still unknown. Previously, using a human epidermal growth factor receptor - Ret chimaeric receptor (HERRet) stably transfected into fibroblasts, it was shown that Ret activation induces the activation of p21ras, but, surprisingly, activation of extracellular signal-regulated kinase 2 (ERK2) was not observed (Santoro et al. (1994) Mol. Cell. Biol., 14, 663). In this report we describe early signaling events induced by the activated HERRet fusion receptor in a cell line derived from neuroectodermal tissue, SK-N-MC. In these cells, activated HERRet induces tyrosine phosphorylation of Shc, complex formation of Shc with Grb2 and Sos and activation of p21ras. Importantly, also ERK2 is activated. This activation was strong and sustained for at least 2 h. Activation was abolished by the dominant negative p21rasasn17 mutant, showing that activation of ERK2 is mediated by p21ras. These results suggest that Ret can induce ERK2 activation in a p21ras dependent manner in cells derived from tissue where Ret is endogenously expressed.
Ret是一种受体酪氨酸激酶，主要表达于源自神经外胚层的组织中，与2A型和2B型多发性内分泌肿瘤、家族性甲状腺髓样癌以及先天性巨结肠病有关。该受体的配体仍不清楚。以前，通过将人表皮生长因子受体-Ret嵌合受体（HERRet）稳定转染到成纤维细胞中，发现Ret激活可诱导p21ras的激活，但令人惊讶的是，未观察到细胞外信号调节激酶2（ERK2）的激活（Santoro等人，（1994年）《分子细胞生物学》，14卷，663页）。在本报告中，我们描述了在源自神经外胚层组织的细胞系SK-N-MC中，由激活的HERRet融合受体诱导的早期信号事件。在这些细胞中，激活的HERRet诱导Shc的酪氨酸磷酸化、Shc与Grb2和Sos的复合物形成以及p21ras的激活。重要的是，ERK2也被激活。这种激活很强且持续至少2小时。显性负性p21rasasn17突变体消除了这种激活，表明ERK2的激活是由p21ras介导的。这些结果表明，在Ret内源性表达的组织来源的细胞中，Ret可以以p21ras依赖的方式诱导ERK2激活。
