SHANK proteins limit integrin activation by directly interacting with Rap1 and R-Ras.
SHANK proteins limit integrin activation by directly interacting with Rap1 and R-Ras.
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DOI：
10.1038/ncb3487
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发表时间：
2017-04
影响因子：
21.3
通讯作者：
Ivaska J
中科院分区：
文献类型：
--
作者：
Lilja J;Zacharchenko T;Georgiadou M;Jacquemet G;De Franceschi N;Peuhu E;Hamidi H;Pouwels J;Martens V;Nia FH;Beifuss M;Boeckers T;Kreienkamp HJ;Barsukov IL;Ivaska J
SHANK 3是一种突触支架蛋白和肌动蛋白调节剂，在中枢神经系统外广泛表达，主要功能未知。解析SHANK 3 N-末端区域的结构揭示了SPN-结构域是对GTP结合的Ras和Rap G-蛋白具有高亲和力的意想不到的Ras-缔合结构域。Rap 1在整合素活化中的作用已经很好地确定，但是拮抗它的机制在很大程度上仍然未知。在这里，我们表明SHANK 1和SHANK 3作为整合素激活抑制剂，通过SPN结构域隔离活性Rap 1和R-Ras，从而限制它们在质膜上的生物利用度。因此，SHANK 3沉默触发质膜Rap 1活性增加，细胞扩展，迁移和侵袭。SHANK 3 SPN结构域（R12 C和L 68 P）内的自闭症相关突变破坏了G蛋白相互作用，并未能抵消癌细胞和神经元中沿着Rap 1/RIAM/talin轴的整合素激活。总之，我们建立SHANK作为G蛋白信号传导和整合素依赖性过程的关键调节剂。
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.