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

DOI: 10.1038/ncb3487 DOI Help

Authors: Johanna Lilja (University of Turku) , Thomas Zacharchenko (University of Liverpool) , Maria Georgiadou (University of Turku) , Guillaume Jacquemet (University of Turku) , Nicola de Franceschi (University of Turku) , Emilia Peuhu (University of Turku) , Hellyeh Hamidi (University of Turku) , Jeroen Pouwels (University of Turku) , Victoria Martens (University Medical Center Hamburg-Eppendorf) , Fatemeh hassani Nia (University Medical Center Hamburg-Eppendorf) , Malte Beifuss (University Medical Center Hamburg-Eppendorf) , Tobias Boeckers (University of Ulm) , Hans-Juergen Kreienkamp (University Medical Center Hamburg-Eppendorf) , Igor l. Barsukov (University of Liverpool) , Johanna Ivaska (University of Turku)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Nature Cell Biology , VOL 19 , PAGES 292 - 305

State: Published (Approved)
Published: March 2017

Abstract: 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.

Journal Keywords: Cell migration; Integrins

Diamond Keywords: Autism; Breast Cancer

Subject Areas: Biology and Bio-materials

Instruments: I04-1-Macromolecular Crystallography (fixed wavelength)

Added On: 19/04/2017 10:20

Discipline Tags:

Non-Communicable Diseases Health & Wellbeing Cancer Neurology Structural biology Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)