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

被引：1

作者：

Weidner, Philip ^{[1
]}

Saar, Daniel ^{[2
,3
]}

Soehn, Michaela ^{[1
]}

Schroeder, Torsten ^{[1
]}

Yu, Yanxiong ^{[1
]}

Zoellner, Frank G. ^{[4
,5
,6
]}

Ponelies, Norbert ^{[7
]}

Zhou, Xiaobo ^{[8
]}

Zwicky, Andre ^{[9
]}

Rohrbacher, Florian N. ^{[9
]}

Pattabiraman, Vijaya R. ^{[9
]}

Tanriver, Matthias ^{[9
]}

Bauer, Alexander ^{[2
,3
]}

Ahmed, Hazem ^{[10
]}

Ametamey, Simon M. ^{[10
]}

Riffel, Philipp ^{[11
]}

Seger, Rony ^{[12
]}

Bode, Jeffrey W. ^{[9
]}

Wade, Rebecca C. ^{[13
,14
,15
]}

Ebert, Matthias P. A. ^{[1
,16
]}

Kragelund, Birthe B. ^{[2
,3
,18
,19
]}

Burgermeister, Elke ^{[1
,17
]}

机构：

[1] Heidelberg Univ, Med Fac Mannheim, Dept Med 2, Mannheim, Germany

[2] Univ Copenhagen, Struct Biol & NMR Lab SBiNLab, Copenhagen, Denmark

[3] Univ Copenhagen, Linderstrom Lang Ctr Prot Sci, Dept Biol, Copenhagen, Denmark

[4] Heidelberg Univ, Med Fac Mannheim, Comp Assisted Clin Med, Mannheim, Germany

[5] Heidelberg Univ, Mannheim Inst Intelligent Syst Med, Med Fac Mannheim, Mannheim, Germany

[6] Heidelberg Univ, Med Fac Mannheim, Cooperat Core Facil Anim Scanner ZI, Mannheim, Germany

[7] Heidelberg Univ, Med Fac Mannheim, Orthopaed & Trauma Surg, Mannheim, Germany

[8] Heidelberg Univ, Med Fac Mannheim, Dept Med 1, Mannheim, Germany

[9] ETH, Lab Organ Chem, Dept Chem & Appl Biosci, Zurich, Switzerland

[10] ETH, Inst Pharmaceut Sci, Dept Chem & Appl Biosci, Zurich, Switzerland

[11] Heidelberg Univ, Med Fac Mannheim, Clin Radiol & Nucl Med, Mannheim, Germany

[12] Weizmann Inst Sci, Dept Immunol & Regenerat Biol, Rehovot, Israel

[13] Heidelberg Inst Theoret Studies HITS, Heidelberg, Germany

[14] Heidelberg Univ, Zentrum Mol Biol ZMBH, DKFZ ZMBH Alliance, Heidelberg, Germany

[15] Heidelberg Univ, Interdisciplinary Ctr Sci Comp IWR, Heidelberg, Germany

[16] Univ Med Ctr, DKFZ Hector Inst, Mannheim, Germany

[17] Heidelberg Univ, Univ Klinikum Mannheim, Med Fac Mannheim, Dept Med 2, Theodor Kutzer Ufer 1-3, D-68167 Mannheim, Germany

[18] Linderstrom Lang Ctr Prot Sci, REPIN, Ole Maaloes Vej 5, DK-2200 Copenhagen N, Denmark

[19] Struct Biol & NMR Lab, Ole Maaloes Vej 5, DK-2200 Copenhagen N, Denmark

来源：

CANCER LETTERS | 2024年 / 588卷

关键词：

Colorectal cancer; RAS; MTMR7; Phosphatase; Myotubularin; Peptide; Coiled coil; NMR; HELICAL PEPTIDES; FOLDING PROBLEM; KRAS; PROTEINS; DYNAMICS; KINASES; DOMAIN; CELLS; MODEL; LINE;

D O I：

10.1016/j.canlet.2024.216783

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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-RAS G12V 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.

引用

页数：19

共 32 条

[31] NMR 1H,13C, 15N backbone and 13C side chain resonance assignment of the G12C mutant of human K-Ras bound to GDP
Sharma, Alok K.
Lee, Seung-Joo
Rigby, Alan C.
Townson, Sharon A.
BIOMOLECULAR NMR ASSIGNMENTS, 2018, 12 (02) : 269 - 272
[32] NMR 1H,13C, 15N backbone and 13C side chain resonance assignment of the G12C mutant of human K-Ras bound to GDP
Alok K. Sharma
Seung-Joo Lee
Alan C. Rigby
Sharon A. Townson
Biomolecular NMR Assignments, 2018, 12 : 269 - 272

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