相关受体酪氨酸激酶 RON 和 MET 通过 Gab1 和 Grb2 衔接蛋白在信号转导中呈现不同的参与。
Distinct involvement of the Gab1 and Grb2 adaptor proteins in signal transduction by the related receptor tyrosine kinases RON and MET.
机构信息
Department of Molecular Oncology, Genentech, Inc, South San Francisco, California 94080, USA.
出版信息
J Biol Chem. 2011 Sep 16;286(37):32762-74. doi: 10.1074/jbc.M111.239384. Epub 2011 Jul 22.
Abstract
Although the signal transduction mechanisms of the receptor tyrosine kinase MET are well defined, less is known about its close relative RON. MET initiates intracellular signaling by autophosphorylation on specific cytoplasmic tyrosines that form docking sites for the adaptor proteins Grb2 and Gab1. Grb2 binds directly and is essential for all of the biological activities of MET. Gab1 docks either directly or indirectly via Grb2 and controls only a subset of MET functions. Because MET and RON possess similar adaptor binding sites, it was anticipated that their adaptor interactions would be conserved. Here we show that in contrast to MET, RON relies primarily on Gab1 for signal transmission. Surprisingly, disruption of the Grb2 docking site of RON or Grb2 depletion augments activity, whereas enhancement of Grb2 binding attenuates Gab1 recruitment and signaling. Hence, RON and MET differ in their adaptor interactions; furthermore, Grb2 performs a novel antagonistic role in the context of RON signaling.
摘要
虽然受体酪氨酸激酶 MET 的信号转导机制已经得到很好的定义，但对于其近亲 RON 的了解较少。MET 通过自身磷酸化特定的细胞质酪氨酸来启动细胞内信号转导，这些酪氨酸形成衔接蛋白 Grb2 和 Gab1 的对接位点。Grb2 直接结合并对 MET 的所有生物学活性都是必需的。Gab1 通过 Grb2 直接或间接对接，仅控制 MET 功能的一部分。由于 MET 和 RON 具有相似的衔接蛋白结合位点，因此预计它们的衔接蛋白相互作用将是保守的。在这里，我们表明与 MET 相反，RON 主要依赖 Gab1 进行信号传递。令人惊讶的是，RON 的 Grb2 对接位点的破坏或 Grb2 的耗竭增强了活性，而 Grb2 结合的增强则减弱了 Gab1 的募集和信号转导。因此，RON 和 MET 在衔接蛋白相互作用上存在差异；此外，Grb2 在 RON 信号转导的背景下发挥了新的拮抗作用。
相似文献
1
Distinct involvement of the Gab1 and Grb2 adaptor proteins in signal transduction by the related receptor tyrosine kinases RON and MET.相关受体酪氨酸激酶 RON 和 MET 通过 Gab1 和 Grb2 衔接蛋白在信号转导中呈现不同的参与。
J Biol Chem. 2011 Sep 16;286(37):32762-74. doi: 10.1074/jbc.M111.239384. Epub 2011 Jul 22.
2
Identification of an atypical Grb2 carboxyl-terminal SH3 domain binding site in Gab docking proteins reveals Grb2-dependent and -independent recruitment of Gab1 to receptor tyrosine kinases.在Gab对接蛋白中鉴定出非典型的Grb2羧基末端SH3结构域结合位点，揭示了Gab1通过Grb2依赖性和非依赖性方式募集到受体酪氨酸激酶。
J Biol Chem. 2000 Oct 6;275(40):31536-45. doi: 10.1074/jbc.M003597200.
3
Coupling of Gab1 to c-Met, Grb2, and Shp2 mediates biological responses.Gab1与c-Met、Grb2和Shp2的偶联介导生物学反应。
J Cell Biol. 2000 Jun 26;149(7):1419-32. doi: 10.1083/jcb.149.7.1419.
4
Gab1 coupling to the HGF/Met receptor multifunctional docking site requires binding of Grb2 and correlates with the transforming potential.Gab1与HGF/Met受体多功能对接位点的偶联需要Grb2的结合，且与转化潜能相关。
Oncogene. 1997 Dec 18;15(25):3103-11. doi: 10.1038/sj.onc.1201561.
5
Anti-apoptotic role of caspase-cleaved GAB1 adaptor protein in hepatocyte growth factor/scatter factor-MET receptor protein signaling.半胱氨酸天冬氨酸蛋白酶剪切的 GAB1 衔接蛋白在肝细胞生长因子/分散因子-MET 受体蛋白信号中的抗凋亡作用。
J Biol Chem. 2012 Oct 12;287(42):35382-35396. doi: 10.1074/jbc.M112.409797. Epub 2012 Aug 22.
6
Association of the multisubstrate docking protein Gab1 with the hepatocyte growth factor receptor requires a functional Grb2 binding site involving tyrosine 1356.多底物对接蛋白Gab1与肝细胞生长因子受体的结合需要一个涉及酪氨酸1356的功能性Grb2结合位点。
J Biol Chem. 1997 Aug 15;272(33):20811-9. doi: 10.1074/jbc.272.33.20811.
7
Grb2-independent recruitment of Gab1 requires the C-terminal lobe and structural integrity of the Met receptor kinase domain.不依赖Grb2的Gab1募集需要Met受体激酶结构域的C末端叶和结构完整性。
J Biol Chem. 2003 Aug 8;278(32):30083-90. doi: 10.1074/jbc.M302675200. Epub 2003 May 22.
8
Interaction between Gab1 and the c-Met receptor tyrosine kinase is responsible for epithelial morphogenesis.Gab1与c-Met受体酪氨酸激酶之间的相互作用负责上皮形态发生。
Nature. 1996 Nov 14;384(6605):173-6. doi: 10.1038/384173a0.
9
ShcA and Grb2 mediate polyoma middle T antigen-induced endothelial transformation and Gab1 tyrosine phosphorylation.ShcA和Grb2介导多瘤病毒中T抗原诱导的内皮细胞转化以及Gab1酪氨酸磷酸化。
EMBO J. 2001 Nov 15;20(22):6327-36. doi: 10.1093/emboj/20.22.6327.
10
MUC20 suppresses the hepatocyte growth factor-induced Grb2-Ras pathway by binding to a multifunctional docking site of met.MUC20通过与met的多功能对接位点结合来抑制肝细胞生长因子诱导的Grb2-Ras途径。
Mol Cell Biol. 2004 Sep;24(17):7456-68. doi: 10.1128/MCB.24.17.7456-7468.2004.
引用本文的文献
1
MSP-RON signaling in liver pathobiology and as an emerging therapeutic target: a review of the current evidence.MSP-RON信号通路在肝脏病理生物学中的作用及作为新兴治疗靶点的研究现状：现有证据综述
Cell Commun Signal. 2025 Aug 28;23(1):385. doi: 10.1186/s12964-025-02407-5.
2
EGFR transactivates RON to drive oncogenic crosstalk.EGFR 反式激活 RON 以驱动致癌性串扰。
Elife. 2021 Nov 25;10:e63678. doi: 10.7554/eLife.63678.
3
RON and MET Co-overexpression Are Significant Pathological Characteristics of Poor Survival and Therapeutic Targets of Tyrosine Kinase Inhibitors in Triple-Negative Breast Cancer.RON 和 MET 共表达是三阴性乳腺癌不良生存的重要病理特征，也是酪氨酸激酶抑制剂治疗靶点。
Cancer Res Treat. 2020 Jul;52(3):973-986. doi: 10.4143/crt.2019.726. Epub 2020 Apr 22.
4
Ron Receptor Signaling Ameliorates Hepatic Fibrosis in a Diet-Induced Nonalcoholic Steatohepatitis Mouse Model.RON 受体信号转导改善饮食诱导的非酒精性脂肪性肝炎小鼠模型的肝纤维化。
J Proteome Res. 2018 Sep 7;17(9):3268-3280. doi: 10.1021/acs.jproteome.8b00379. Epub 2018 Aug 23.
5
Function of the c-Met receptor tyrosine kinase in carcinogenesis and associated therapeutic opportunities.c-Met 受体酪氨酸激酶在肿瘤发生中的作用及相关治疗机会。
Mol Cancer. 2018 Feb 19;17(1):45. doi: 10.1186/s12943-018-0796-y.
6
Expression of Hepatocyte Growth Factor-Like Protein in Human Wound Tissue and Its Biological Functionality in Human Keratinocytes.肝细胞生长因子样蛋白在人伤口组织中的表达及其在人角质形成细胞中的生物学功能
Biomedicines. 2015 Feb 4;3(1):110-123. doi: 10.3390/biomedicines3010110.
7
Cleavage of Grb2-Associated Binding Protein 2 by Viral Proteinase 2A during Infection.感染期间病毒蛋白酶2A对Grb2相关结合蛋白2的切割作用。
Front Cell Infect Microbiol. 2017 Mar 16;7:85. doi: 10.3389/fcimb.2017.00085. eCollection 2017.
8
Palmitoylation regulates the intracellular trafficking and stability of c-Met.棕榈酰化调节c-Met的细胞内运输和稳定性。
Oncotarget. 2016 May 31;7(22):32664-77. doi: 10.18632/oncotarget.8706.
9
MET Suppresses Epithelial VEGFR2 via Intracrine VEGF-induced Endoplasmic Reticulum-associated Degradation.MET 通过内源性 VEGF 诱导的内质网相关降解来抑制上皮 VEGFR2。
EBioMedicine. 2015 Mar 28;2(5):406-20. doi: 10.1016/j.ebiom.2015.03.021. eCollection 2015 May.
10
Roles of c-Met and RON kinases in tumor progression and their potential as therapeutic targets.c-Met和RON激酶在肿瘤进展中的作用及其作为治疗靶点的潜力。
Oncotarget. 2015 Feb 28;6(6):3507-18. doi: 10.18632/oncotarget.3420.
本文引用的文献
1
Cell signaling by receptor tyrosine kinases.受体酪氨酸激酶的细胞信号转导。
Cell. 2010 Jun 25;141(7):1117-34. doi: 10.1016/j.cell.2010.06.011.
2
The macrophage stimulating protein/Ron pathway as a potential therapeutic target to impede multiple mechanisms involved in breast cancer progression.巨噬细胞刺激蛋白/Ron 通路作为一个潜在的治疗靶点，可抑制乳腺癌进展中涉及的多种机制。
Curr Drug Targets. 2010 Sep;11(9):1157-68. doi: 10.2174/138945010792006825.
3
The molecular pathology of cancer.癌症的分子病理学。
Nat Rev Clin Oncol. 2010 May;7(5):251-65. doi: 10.1038/nrclinonc.2010.41. Epub 2010 Mar 30.
4
Kinase mutations in human disease: interpreting genotype-phenotype relationships.人类疾病中的激酶突变：解读基因型-表型关系。
Nat Rev Genet. 2010 Jan;11(1):60-74. doi: 10.1038/nrg2707.
5
Cell signaling in space and time: where proteins come together and when they're apart.细胞信号转导的时空机制：蛋白质的聚合与解离。
Science. 2009 Nov 27;326(5957):1220-4. doi: 10.1126/science.1175668.
6
Kinome signaling through regulated protein-protein interactions in normal and cancer cells.在正常细胞和癌细胞中，通过调控蛋白质-蛋白质相互作用实现激酶组信号传导。
Curr Opin Cell Biol. 2009 Apr;21(2):147-53. doi: 10.1016/j.ceb.2009.02.005. Epub 2009 Mar 18.
7
The precise sequence of FGF receptor autophosphorylation is kinetically driven and is disrupted by oncogenic mutations.成纤维细胞生长因子（FGF）受体自身磷酸化的精确序列受动力学驱动，并被致癌突变破坏。
Sci Signal. 2009 Feb 17;2(58):ra6. doi: 10.1126/scisignal.2000021.
8
A new mechanism for the regulation of Gab1 recruitment to the plasma membrane.一种调节Gab1募集至质膜的新机制。
J Cell Sci. 2009 Jan 1;122(Pt 1):55-64. doi: 10.1242/jcs.037226. Epub 2008 Dec 2.
9
Gab1 but not Grb2 mediates tumor progression in Met overexpressing colorectal cancer cells.在Met过表达的结肠癌细胞中，Gab1而非Grb2介导肿瘤进展。
Carcinogenesis. 2008 Mar;29(3):647-55. doi: 10.1093/carcin/bgn009. Epub 2008 Jan 12.
10
Roles for deregulated receptor tyrosine kinases and their downstream signaling molecules in hematologic malignancies.失调的受体酪氨酸激酶及其下游信号分子在血液系统恶性肿瘤中的作用。
Cancer Sci. 2008 Mar;99(3):479-85. doi: 10.1111/j.1349-7006.2007.00717.x. Epub 2008 Jan 2.
Zotero 插件