Chang C M, Shu H K, Kung H J
Department of Molecular Biology and Microbiology, Case Western Reserve University, School of Medicine, Cleveland, OH 44106, USA.
Proc Natl Acad Sci U S A. 1995 Apr 25;92(9):3928-32. doi: 10.1073/pnas.92.9.3928.
src and erbB are two tyrosine kinase-encoding oncogenes carried by retroviruses, which have distinct disease specificities. The former induces predominantly sarcomas, and the latter, leukemias. Src and ErbB have similar catalytic domains but have very different regulatory domains. A wealth of information exists concerning how different regulatory domains [Src homology 2 (SH2) and SH3 domains and autophosphorylation sites] control substrate and disease specificities. Whether the catalytic domain helps determine these specificities remains to be explored. Here we show that the Src catalytic domain is enzymatically active when substituted into the ErbB backbone and interacts with the ErbB regulatory domain. This ErbB/Src chimera displays autophosphorylation and substrate phosphorylation patterns different from those of both Src and ErbB. Neither SH2 and SH3 nor autophosphorylation sites are required for the Src catalytic domain to exert its fibroblast transforming ability. Most significantly, the catalytic domain can convert erbB from a leukemogenic oncogene into a sarcomagenic oncogene, suggesting that the leukemogenic determinants in part reside within the ErbB catalytic domain.
Src和erbB是逆转录病毒携带的两个编码酪氨酸激酶的癌基因，它们具有不同的疾病特异性。前者主要诱导肉瘤，后者诱导白血病。Src和ErbB具有相似的催化结构域，但调控结构域却大不相同。关于不同的调控结构域（Src同源2结构域即SH2结构域、SH3结构域和自身磷酸化位点）如何控制底物和疾病特异性，已有大量信息。催化结构域是否有助于确定这些特异性仍有待探索。在此我们表明，Src催化结构域被替换到ErbB骨架中时具有酶活性，并与ErbB调控结构域相互作用。这种ErbB/Src嵌合体显示出与Src和ErbB均不同的自身磷酸化和底物磷酸化模式。Src催化结构域发挥其成纤维细胞转化能力既不需要SH2和SH3结构域，也不需要自身磷酸化位点。最为重要的是，催化结构域可将erbB从致白血病癌基因转变为致肉瘤癌基因，这表明致白血病决定因素部分存在于ErbB催化结构域中。
