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

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SHANK proteins limit integrin activation by directly interacting with Rap1 and R-Ras. / Lilja, Johanna; Zacharchenko, Thomas; Georgiadou, Maria; Jacquemet, Guillaume; Franceschi, Nicola De; Peuhu, Emilia; Hamidi, Hellyeh; Pouwels, Jeroen; Martens, Victoria; Nia, Fatemeh Hassani ; Beifuss, Malte ; Boeckers, Tobias M; Kreienkamp, Hans-Juergen; Barsukov, Igor L; Ivaska, Johanna.

In: NAT CELL BIOL, Vol. 19, No. 4, 04.2017, p. 292-305.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

Lilja, J, Zacharchenko, T, Georgiadou, M, Jacquemet, G, Franceschi, ND, Peuhu, E, Hamidi, H, Pouwels, J, Martens, V, Nia, FH, Beifuss, M, Boeckers, TM, Kreienkamp, H-J, Barsukov, IL & Ivaska, J 2017, 'SHANK proteins limit integrin activation by directly interacting with Rap1 and R-Ras', NAT CELL BIOL, vol. 19, no. 4, pp. 292-305. https://doi.org/10.1038/ncb3487

APA

Lilja, J., Zacharchenko, T., Georgiadou, M., Jacquemet, G., Franceschi, N. D., Peuhu, E., Hamidi, H., Pouwels, J., Martens, V., Nia, F. H., Beifuss, M., Boeckers, T. M., Kreienkamp, H-J., Barsukov, I. L., & Ivaska, J. (2017). SHANK proteins limit integrin activation by directly interacting with Rap1 and R-Ras. NAT CELL BIOL, 19(4), 292-305. https://doi.org/10.1038/ncb3487

Vancouver

Lilja J, Zacharchenko T, Georgiadou M, Jacquemet G, Franceschi ND, Peuhu E et al. SHANK proteins limit integrin activation by directly interacting with Rap1 and R-Ras. NAT CELL BIOL. 2017 Apr;19(4):292-305. https://doi.org/10.1038/ncb3487

Bibtex

@article{e6e84acbd836492286b599ad3de2930c,
title = "SHANK proteins limit integrin activation by directly interacting with Rap1 and R-Ras",
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.",
keywords = "Journal Article, POM-Newsletter",
author = "Johanna Lilja and Thomas Zacharchenko and Maria Georgiadou and Guillaume Jacquemet and Franceschi, {Nicola De} and Emilia Peuhu and Hellyeh Hamidi and Jeroen Pouwels and Victoria Martens and Nia, {Fatemeh Hassani} and Malte Beifuss and Boeckers, {Tobias M} and Hans-Juergen Kreienkamp and Barsukov, {Igor L} and Johanna Ivaska",
year = "2017",
month = apr,
doi = "10.1038/ncb3487",
language = "English",
volume = "19",
pages = "292--305",
journal = "NAT CELL BIOL",
issn = "1465-7392",
publisher = "NATURE PUBLISHING GROUP",
number = "4",

}

RIS

TY - JOUR

T1 - SHANK proteins limit integrin activation by directly interacting with Rap1 and R-Ras

AU - Lilja, Johanna

AU - Zacharchenko, Thomas

AU - Georgiadou, Maria

AU - Jacquemet, Guillaume

AU - Franceschi, Nicola De

AU - Peuhu, Emilia

AU - Hamidi, Hellyeh

AU - Pouwels, Jeroen

AU - Martens, Victoria

AU - Nia, Fatemeh Hassani

AU - Beifuss, Malte

AU - Boeckers, Tobias M

AU - Kreienkamp, Hans-Juergen

AU - Barsukov, Igor L

AU - Ivaska, Johanna

PY - 2017/4

Y1 - 2017/4

N2 - 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.

AB - 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.

KW - Journal Article

KW - POM-Newsletter

U2 - 10.1038/ncb3487

DO - 10.1038/ncb3487

M3 - SCORING: Journal article

C2 - 28263956

VL - 19

SP - 292

EP - 305

JO - NAT CELL BIOL

JF - NAT CELL BIOL

SN - 1465-7392

IS - 4

ER -