作用于整合素的癌基因:SHANK
  • SHANK3广泛表达于中枢神经系统外的人体组织,功能未知;
  • SHANK3蛋白N末端区域的结构显示,SPN结构域是一个Ras相关结构域;
  • Rap1在整合素活化中的作用已很明确,抑制机制未知;
  • SHANK1和SHANK3作为整合素激活抑制剂通过SPN结构域隔离活性Rap1和R-Ras,限制了他们在质膜上的生物利用度;
  • 沉默SHANK3基因诱发质膜上Rap1活性增加、细胞扩散、迁移和侵袭;SHANK3的SPN结构域上的自闭症相关突变破坏了G蛋白相互作用,不能阻止整合素激活。
关键字
延伸阅读本研究的原文信息和链接出处,以及相关解读和评论文章。欢迎读者朋友们推荐!
图片
Nature Cell Biology [IF:20.042]

SHANK proteins limit integrin activation by directly interacting with Rap1 and R-Ras

SHANK蛋白通过直接与Rap1和R-Ras相互作用来限制整合素的激活

10.1038/ncb3487

2017-03-06, Article

Abstract & Authors:展开

Abstract:收起
SHANK3, a synaptic scaffold protein and actin regulator, is widely expressed outside of the central nervous system with predominantly unknown function. Solving the structure of the SHANK3 N-terminal region revealed that the SPN domain is an unexpected Ras-association domain with high affinity for GTP-bound Ras and Rap G-proteins. The role of Rap1 in integrin activation is well established but the mechanisms to antagonize it remain largely unknown. Here, we show that SHANK1 and SHANK3 act as integrin activation inhibitors by sequestering active Rap1 and R-Ras via the SPN domain and thus limiting their bioavailability at the plasma membrane. Consistently, SHANK3 silencing triggers increased plasma membrane Rap1 activity, cell spreading, migration and invasion. Autism-related mutations within the SHANK3 SPN domain (R12C and L68P) disrupt G-protein interaction and fail to counteract integrin activation along the Rap1-RIAM-talin axis in cancer cells and neurons. Altogether, we establish SHANKs as critical regulators of G-protein signalling and integrin-dependent processes.

First Authors:
Johanna Lilja,Thomas Zacharchenko

Correspondence Authors:
Hans-Juergen Kreienkamp,Igor L Barsukov,Johanna Ivaska

All Authors:
Johanna Lilja,Thomas Zacharchenko,Maria Georgiadou,Guillaume Jacquemet,Nicola De Franceschi,Emilia Peuhu,Hellyeh Hamidi,Jeroen Pouwels,Victoria Martens,Fatemeh Hassani Nia,Malte Beifuss,Tobias Boeckers,Hans-Juergen Kreienkamp,Igor L Barsukov,Johanna Ivaska

评论