Myotubularin-related-protein-7 inhibits mutant (G12V) K-RAS by direct interaction

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt

Standard

Myotubularin-related-protein-7 inhibits mutant (G12V) K-RAS by direct interaction. / Weidner, Philip; Saar, Daniel; Söhn, Michaela; Schroeder, Torsten; Yu, Yanxiong; Zöllner, Frank G.; Ponelies, Norbert; Zhou, Xiaobo; Zwicky, André; Rohrbacher, Florian N.; Pattabiraman, Vijaya R.; Tanriver, Matthias; Bauer, Alexander; Ahmed, Hazem; Ametamey, Simon M.; Riffel, Philipp; Seger, Rony; Bode, Jeffrey W.; Wade, Rebecca C.; Ebert, Matthias P.A.; Kragelund, Birthe B.; Burgermeister, Elke.

I: Cancer Letters, Bind 588, 216783, 2024.

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt

Harvard

Weidner, P, Saar, D, Söhn, M, Schroeder, T, Yu, Y, Zöllner, FG, Ponelies, N, Zhou, X, Zwicky, A, Rohrbacher, FN, Pattabiraman, VR, Tanriver, M, Bauer, A, Ahmed, H, Ametamey, SM, Riffel, P, Seger, R, Bode, JW, Wade, RC, Ebert, MPA, Kragelund, BB & Burgermeister, E 2024, 'Myotubularin-related-protein-7 inhibits mutant (G12V) K-RAS by direct interaction', Cancer Letters, bind 588, 216783. https://doi.org/10.1016/j.canlet.2024.216783

APA

Weidner, P., Saar, D., Söhn, M., Schroeder, T., Yu, Y., Zöllner, F. G., Ponelies, N., Zhou, X., Zwicky, A., Rohrbacher, F. N., Pattabiraman, V. R., Tanriver, M., Bauer, A., Ahmed, H., Ametamey, S. M., Riffel, P., Seger, R., Bode, J. W., Wade, R. C., ... Burgermeister, E. (2024). Myotubularin-related-protein-7 inhibits mutant (G12V) K-RAS by direct interaction. Cancer Letters, 588, [216783]. https://doi.org/10.1016/j.canlet.2024.216783

Vancouver

Weidner P, Saar D, Söhn M, Schroeder T, Yu Y, Zöllner FG o.a. Myotubularin-related-protein-7 inhibits mutant (G12V) K-RAS by direct interaction. Cancer Letters. 2024;588. 216783. https://doi.org/10.1016/j.canlet.2024.216783

Author

Weidner, Philip ; Saar, Daniel ; Söhn, Michaela ; Schroeder, Torsten ; Yu, Yanxiong ; Zöllner, Frank G. ; Ponelies, Norbert ; Zhou, Xiaobo ; Zwicky, André ; Rohrbacher, Florian N. ; Pattabiraman, Vijaya R. ; Tanriver, Matthias ; Bauer, Alexander ; Ahmed, Hazem ; Ametamey, Simon M. ; Riffel, Philipp ; Seger, Rony ; Bode, Jeffrey W. ; Wade, Rebecca C. ; Ebert, Matthias P.A. ; Kragelund, Birthe B. ; Burgermeister, Elke. / Myotubularin-related-protein-7 inhibits mutant (G12V) K-RAS by direct interaction. I: Cancer Letters. 2024 ; Bind 588.

Bibtex

@article{4424e2cf25ce4c9290d1e737ac00b444,

title = "Myotubularin-related-protein-7 inhibits mutant (G12V) K-RAS by direct interaction",

abstract = "Inhibition of K-RAS effectors like B-RAF or MEK1/2 is accompanied by treatment resistance in cancer patients via re-activation of PI3K and Wnt signaling. We hypothesized that myotubularin-related-protein-7 (MTMR7), which inhibits PI3K and ERK1/2 signaling downstream of RAS, directly targets RAS and thereby prevents resistance. Using cell and structural biology combined with animal studies, we show that MTMR7 binds and inhibits RAS at cellular membranes. Overexpression of MTMR7 reduced RAS GTPase activities and protein levels, ERK1/2 phosphorylation, c-FOS transcription and cancer cell proliferation in vitro. We located the RAS-inhibitory activity of MTMR7 to its charged coiled coil (CC) region and demonstrate direct interaction with the gastrointestinal cancer-relevant K-RASG12V mutant, favouring its GDP-bound state. In mouse models of gastric and intestinal cancer, a cell-permeable MTMR7-CC mimicry peptide decreased tumour growth, Ki67 proliferation index and ERK1/2 nuclear positivity. Thus, MTMR7 mimicry peptide(s) could provide a novel strategy for targeting mutant K-RAS in cancers.",

keywords = "Coiled coil, Colorectal cancer, MTMR7, Myotubularin, NMR, Peptide, Phosphatase, RAS",

author = "Philip Weidner and Daniel Saar and Michaela S{\"o}hn and Torsten Schroeder and Yanxiong Yu and Z{\"o}llner, {Frank G.} and Norbert Ponelies and Xiaobo Zhou and Andr{\'e} Zwicky and Rohrbacher, {Florian N.} and Pattabiraman, {Vijaya R.} and Matthias Tanriver and Alexander Bauer and Hazem Ahmed and Ametamey, {Simon M.} and Philipp Riffel and Rony Seger and Bode, {Jeffrey W.} and Wade, {Rebecca C.} and Ebert, {Matthias P.A.} and Kragelund, {Birthe B.} and Elke Burgermeister",

note = "Publisher Copyright: {\textcopyright} 2024 The Authors",

year = "2024",

doi = "10.1016/j.canlet.2024.216783",

language = "English",

volume = "588",

journal = "Cancer Letters",

issn = "0304-3835",

publisher = "Elsevier Ireland Ltd",

}

RIS

TY - JOUR

T1 - Myotubularin-related-protein-7 inhibits mutant (G12V) K-RAS by direct interaction

AU - Weidner, Philip

AU - Saar, Daniel

AU - Söhn, Michaela

AU - Schroeder, Torsten

AU - Yu, Yanxiong

AU - Zöllner, Frank G.

AU - Ponelies, Norbert

AU - Zhou, Xiaobo

AU - Zwicky, André

AU - Rohrbacher, Florian N.

AU - Pattabiraman, Vijaya R.

AU - Tanriver, Matthias

AU - Bauer, Alexander

AU - Ahmed, Hazem

AU - Ametamey, Simon M.

AU - Riffel, Philipp

AU - Seger, Rony

AU - Bode, Jeffrey W.

AU - Wade, Rebecca C.

AU - Ebert, Matthias P.A.

AU - Kragelund, Birthe B.

AU - Burgermeister, Elke

PY - 2024

Y1 - 2024

N2 - Inhibition of K-RAS effectors like B-RAF or MEK1/2 is accompanied by treatment resistance in cancer patients via re-activation of PI3K and Wnt signaling. We hypothesized that myotubularin-related-protein-7 (MTMR7), which inhibits PI3K and ERK1/2 signaling downstream of RAS, directly targets RAS and thereby prevents resistance. Using cell and structural biology combined with animal studies, we show that MTMR7 binds and inhibits RAS at cellular membranes. Overexpression of MTMR7 reduced RAS GTPase activities and protein levels, ERK1/2 phosphorylation, c-FOS transcription and cancer cell proliferation in vitro. We located the RAS-inhibitory activity of MTMR7 to its charged coiled coil (CC) region and demonstrate direct interaction with the gastrointestinal cancer-relevant K-RASG12V mutant, favouring its GDP-bound state. In mouse models of gastric and intestinal cancer, a cell-permeable MTMR7-CC mimicry peptide decreased tumour growth, Ki67 proliferation index and ERK1/2 nuclear positivity. Thus, MTMR7 mimicry peptide(s) could provide a novel strategy for targeting mutant K-RAS in cancers.

AB - Inhibition of K-RAS effectors like B-RAF or MEK1/2 is accompanied by treatment resistance in cancer patients via re-activation of PI3K and Wnt signaling. We hypothesized that myotubularin-related-protein-7 (MTMR7), which inhibits PI3K and ERK1/2 signaling downstream of RAS, directly targets RAS and thereby prevents resistance. Using cell and structural biology combined with animal studies, we show that MTMR7 binds and inhibits RAS at cellular membranes. Overexpression of MTMR7 reduced RAS GTPase activities and protein levels, ERK1/2 phosphorylation, c-FOS transcription and cancer cell proliferation in vitro. We located the RAS-inhibitory activity of MTMR7 to its charged coiled coil (CC) region and demonstrate direct interaction with the gastrointestinal cancer-relevant K-RASG12V mutant, favouring its GDP-bound state. In mouse models of gastric and intestinal cancer, a cell-permeable MTMR7-CC mimicry peptide decreased tumour growth, Ki67 proliferation index and ERK1/2 nuclear positivity. Thus, MTMR7 mimicry peptide(s) could provide a novel strategy for targeting mutant K-RAS in cancers.

KW - Coiled coil

KW - Colorectal cancer

KW - MTMR7

KW - Myotubularin

KW - NMR

KW - Peptide

KW - Phosphatase

KW - RAS

U2 - 10.1016/j.canlet.2024.216783

DO - 10.1016/j.canlet.2024.216783

M3 - Journal article

C2 - 38462034

AN - SCOPUS:85188177959

VL - 588

JO - Cancer Letters

JF - Cancer Letters

SN - 0304-3835

M1 - 216783

ER -

ID: 386374960

Biologisk Institut