The ROR1 pseudokinase diversifies signaling outputs in MET-addicted cancer cells
The ROR1 pseudokinase diversifies signaling outputs in MET-addicted cancer cells
复制标题
DOI：
10.1002/ijc.28879
复制
发表时间：
2014-11-15
影响因子：
6.4
通讯作者：
Comoglio, Paolo Maria
中科院分区：
文献类型：
--
作者：
Gentile, Alessandra;Lazzari, Luca;Comoglio, Paolo Maria
MET是控制驱动增殖、凋亡保护和侵袭的遗传程序的主基因。ROR 1假激酶作为MET底物。然而，其对MET信号传导和MET依赖性生物学结果的贡献仍有待阐明。通过对ROR 1突变体的结构-功能分析，我们发现ROR 1包含两个主要的底物区域：一个位于富含脯氨酸的结构域，并被MET直接磷酸化;另一个位于假激酶结构域，并通过SRC的中间活化而磷酸化。这两个区域的差异磷酸化决定了特异性反应的执行：MET对ROR 1富含脯氨酸的结构域的磷酸化，而SRC对假激酶结构域的磷酸化是必要的，足以控制MET驱动的增殖和保护免于凋亡。因此，富含脯氨酸的结构域和假激酶结构域都介导细胞侵袭。与ROR 1在指定MET依赖性信号的功能后果中的作用一致，ROR 1沉默导致仅一些MET维持的信号转导途径的选择性衰减。这些数据启发了迄今为止难以捉摸的假激酶的功能，并确定了基于致癌激酶的底物特异性的生物多样性机制。
MET is a master gene controlling a genetic program driving proliferation, apoptosis protection and invasion. The ROR1 pseudokinase acts as a MET substrate. However, its contribution to MET signaling and MET-dependent biological outcomes remains to be elucidated. By structure-function analysis of ROR1 mutants, we show that ROR1 encompasses two major substrate regions: one is located in the proline-rich domain and is directly phosphorylated by MET; the other resides in the pseudokinase domain and is phosphorylated through intermediate activation of SRC. Differential phosphorylation of these two regions dictates the execution of specific responses: phosphorylation of the ROR1 proline-rich domain by METbut not phosphorylation of the pseudokinase domain by SRCis necessary and sufficient to control MET-driven proliferation and protection from apoptosis. Differently, both the proline-rich and the pseudokinase domains mediate cell invasion. Consistent with the role of ROR1 in specifying the functional consequences of MET-dependent signals, ROR1 silencing leads to selective attenuation of only some of the signal transduction pathways sustained by MET. These data enlighten the so far elusive function(s) of pseudokinases and identify a mechanism of biological diversification, based on substrate specificity of oncogenic kinases.