Jang Eun Ryoung, Jang HyeIn, Shi Ping, Popa Gabriel, Jeoung Myoungkun, Galperin Emilia
Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY 40536, USA.
Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY 40536, USA
J Cell Sci. 2015 Dec 1;128(23):4428-41. doi: 10.1242/jcs.177543. Epub 2015 Oct 30.
The scaffold protein Shoc2 accelerates activity of the ERK1 and ERK2 (ERK1/2, also known as MAPK3 and MAPK1) pathway. Mutations in Shoc2 result in Noonan-like RASopathy, a developmental disorder with a wide spectrum of symptoms. The amplitude of the ERK1/2 signals transduced through the complex is fine-tuned by the HUWE1-mediated ubiquitylation of Shoc2 and its signaling partner RAF-1. Here, we provide a mechanistic basis of how ubiquitylation of Shoc2 and RAF-1 is controlled. We demonstrate that the newly identified binding partner of Shoc2, the (AAA+) ATPase PSMC5, triggers translocation of Shoc2 to endosomes. At the endosomes, PSMC5 displaces the E3 ligase HUWE1 from the scaffolding complex to attenuate ubiquitylation of Shoc2 and RAF-1. We show that a RASopathy mutation that changes the subcellular distribution of Shoc2 leads to alterations in Shoc2 ubiquitylation due to the loss of accessibility to PSMC5. In summary, our results demonstrate that PSMC5 is a new and important player involved in regulating ERK1/2 signal transmission through the remodeling of Shoc2 scaffold complex in a spatially-defined manner.
支架蛋白Shoc2可加速细胞外信号调节激酶1和2（ERK1/2，也称为丝裂原活化蛋白激酶3和丝裂原活化蛋白激酶1）信号通路的活性。Shoc2基因突变会导致努南样RAS病，这是一种具有广泛症状的发育障碍。通过该复合体转导的ERK1/2信号的幅度由HUWE1介导的Shoc2及其信号伴侣RAF-1的泛素化进行微调。在此，我们提供了Shoc2和RAF-1泛素化如何受到控制的机制基础。我们证明，新发现的Shoc2结合伴侣、（AAA+）ATP酶PSMC5会触发Shoc2向内体的转运。在内体中，PSMC5将E3连接酶HUWE1从支架复合体中置换出来，以减弱Shoc2和RAF-1的泛素化。我们表明，一种改变Shoc2亚细胞分布的RAS病突变会导致Shoc2泛素化改变，这是由于无法接近PSMC5所致。总之，我们的结果表明，PSMC5是通过以空间限定方式重塑Shoc2支架复合体来参与调节ERK1/2信号传递的一个新的重要因子。
