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

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

Oxidative Dimerization of (<i>E</i>)- and (<i>Z</i>)-2-Propenylsesamol with O₂ in the Presence and Absence of Laccases and Other Catalysts: Selective Formation of Carpanones and Benzopyrans under Different Reaction Conditions

The oxidative dimerization of 2-propenylsesamol to carpanone with O₂ as the oxidant, which probably proceeds as a domino phenol oxidation/<i>anti</i>-β,β-radical coupling/intramolecular hetero Diels–Alder reaction, can be efficiently catalyzed by laccases. Experiments with laccases and other catalysts like a Co­(salen) type catalyst and PdCl₂ clearly demonstrate that the diastereoselectivity of the carpanone formation does not depend on the catalyst but on the double-bond geometry of the substrate. With (<i>E</i>)-2-propenylsesamol as the substrate, carpanone and a so far unknown carpanone diastereoisomer are formed in a 9:1 ratio. When (<i>Z</i>)-2-propenylsesamol is used as starting material, carpanone is accompanied by two carpanone diastereoisomers unknown so far in a 5:1:4 ratio. All three carpanone diastereoisomers have been separated by HPLC, and their structures have been elucidated unambiguously by NMR spectroscopy, DFT calculations, and spin work analysis. When the oxidation of 2-propenylsesamol with O₂ is performed in the absence of any catalyst two diastereoisomeric benzopyrans are formed, probably as the result of a domino oxidation/intermolecular hetero Diels–Alder reaction. Under these conditions, carpanone is formed in trace amounts only

Organische Chemie 2004

Bruckner R, Wurthner F, Tschierske C, et al. Organische Chemie 2004. Nachrichten aus der Chemie. 2005;53(3):251-272