Thien C B, Walker F, Langdon W Y
Department of Pathology, University of Western Australia, Western Australia 6009, Crawley, Australia.
Mol Cell. 2001 Feb;7(2):355-65. doi: 10.1016/s1097-2765(01)00183-6.
The c-Cbl protooncogene can function as a negative regulator of receptor protein tyrosine kinases (RPTKs) by targeting activated receptors for polyubiquitination and downregulation. This function requires its tyrosine kinase binding (TKB) domain for targeting RPTKs and RING finger domain to recruit E2 ubiquitin-conjugating enzymes. It has therefore been proposed that oncogenic Cbl proteins act in a dominant-negative manner to block this c-Cbl activity. In testing this hypothesis, we found that although mutations spanning the RING finger abolish c-Cbl-directed polyubiquitination and downregulation of RPTKs, they do not induce transformation. In contrast, it is mutations within a highly conserved alpha-helical structure linking the SH2 and RING finger domains that render Cbl proteins oncogenic. Thus, Cbl transformation involves effects additional to polyubiquitination of RPTKs that are independent of the RING finger and its ability to recruit E2-conjugating enzymes.
原癌基因c-Cbl可作为受体蛋白酪氨酸激酶（RPTK）的负调控因子，通过将活化的受体靶向多聚泛素化和下调来发挥作用。该功能需要其酪氨酸激酶结合（TKB）结构域来靶向RPTK，以及RING指结构域来募集E2泛素结合酶。因此，有人提出致癌性Cbl蛋白以显性负性方式发挥作用，以阻断这种c-Cbl活性。在验证这一假设时，我们发现，尽管跨越RING指的突变消除了c-Cbl介导的RPTK多聚泛素化和下调，但它们不会诱导转化。相反，连接SH2和RING指结构域的高度保守的α螺旋结构内的突变使Cbl蛋白具有致癌性。因此，Cbl转化涉及RPTK多聚泛素化之外的其他效应，这些效应独立于RING指及其募集E2结合酶的能力。
