Santoro M M, Penengo L, Minetto M, Orecchia S, Cilli M, Gaudino G
Dipartimento di Scienze e Tecnologie Avanzate, Università di Torino, Italy.
Oncogene. 1998 Aug 13;17(6):741-9. doi: 10.1038/sj.onc.1201994.
Ron (the receptor for Macrophage Stimulating Protein) has never been implicated before in human malignancies or in cell transformation. In this report we show that Ron can acquire oncogenic potential by means of two amino acid substitutions-D1232V and M1254T-affecting highly conserved residues in the tyrosine kinase domain. The same mutations in Kit and Ret have been found associated with two human malignancies, mastocytosis and Multiple Endocrine Neoplasia type 2B (MEN2B), respectively. Both mutations caused Ron-mediated transformation of 3T3 fibroblasts and tumour formation in nude mice. Moreover, cells transformed by the oncogenic Ron mutants displayed high metastatic potential. The Ron mutant receptors were constitutively active and the catalytic efficiency of the mutated kinase was higher than that of wild-type Ron. Oncogenic Ron mutants enhanced activation of the Ras/MAPK cascade with respect to wild type Ron, without affecting the JNK/SAPK pathway. Expression of Ron mutants in 3T3 fibroblasts led to different patterns of tyrosine-phos-phorylated proteins. These data show that point mutations altering catalytic properties and possibly substrate specificity of the Ron kinase may force cells toward tumorigenesis and metastasis.
Ron（巨噬细胞刺激蛋白受体）此前从未被认为与人类恶性肿瘤或细胞转化有关。在本报告中，我们表明Ron可通过两个氨基酸取代——D1232V和M1254T，影响酪氨酸激酶结构域中高度保守的残基，从而获得致癌潜能。已发现Kit和Ret中的相同突变分别与两种人类恶性肿瘤——肥大细胞增多症和2B型多发性内分泌肿瘤（MEN2B）相关。这两种突变均导致Ron介导的3T3成纤维细胞转化以及裸鼠肿瘤形成。此外，由致癌性Ron突变体转化的细胞具有高转移潜能。Ron突变体受体持续激活，且突变激酶的催化效率高于野生型Ron。与野生型Ron相比，致癌性Ron突变体增强了Ras/MAPK级联反应的激活，而不影响JNK/SAPK途径。Ron突变体在3T3成纤维细胞中的表达导致酪氨酸磷酸化蛋白出现不同模式。这些数据表明，改变Ron激酶催化特性以及可能的底物特异性的点突变可能促使细胞发生肿瘤发生和转移。
