Cellular Response to cMet Endocytosis

细胞对 cMet 内吞作用的反应

基本信息

批准号：
7899862
负责人：
Lisa A. Elferink
金额：
$ 20.82万
依托单位：
UNIVERSITY OF TEXAS MED BR GALVESTON
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-08-30 至 2012-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7899862
关键词：
Adaptor Signaling Protein Address Adenocarcinoma Antibodies Antigens Binding Biochemical Biological Assay Biological Models Cancer Intervention Carcinoma Cell Line Cell Proliferation Cells Chromosomal Rearrangement Clathrin Coated vesicle Collaborations Confocal Microscopy Data Defect Dependence Disease Disseminated Malignant Neoplasm Docking Dominant-Negative Mutation EGF gene Early Diagnosis Early Endosome Endocytosis Epidermal Growth Factor Receptor Epithelial Goals Growth Factor Hepatic Hepatocyte Growth Factor Human Imaging Techniques Immunoprecipitation InlB protein Investigation Kidney Knockout Mice Label Lesion Ligand Binding Ligands Link Listeria Listeria monocytogenes Malignant Neoplasms Malignant neoplasm of pancreas Mediating Mediator of activation protein Metastatic Pancreatic Adenocarcinoma Molecular Multivesicular Body Mutation Neoplasm Metastasis Null Lymphocytes Optics Pancreas Pancreatic Adenocarcinoma Pancreatic carcinoma Pathway interactions Phosphorylation Phosphotransferases Physiological Play Process Property Proteins Proto-Oncogene Protein c-met Receptor Activation Receptor Protein-Tyrosine Kinases Research Personnel Resistance Role Scaffolding Protein Signal Transduction Signaling Molecule Small Interfering RNA Sorting - Cell Movement Specificity Staging Stomach Survival Rate Testing Therapeutic Agents Transferrin Transferrin Receptor Tumor Angiogenesis Ubiquitin Ubiquitination angiogenesis cell growth cell motility cell transformation coated pit conventional therapy design growth factor receptor-bound protein 2 hepatocyte growth factor-regulated tyrosine kinase substrate innovation mutant neoplastic cell novel novel therapeutics outcome forecast pancreatic neoplasm programs receptor receptor internalization response trafficking tumor ubiquitin ligase

项目摘要

DESCRIPTION (provided by applicant): The Hepatocyte Growth Factor Receptor (cMet) is a receptor tyrosine kinase critical for normal cellular responses, such as cell growth, survival and motility. Normally, cMet signaling is tightly regulated. However, increased cMet signaling occurs in many cancers, including pancreatic carcinomas, correlating closely with early-stage invasion, dissemination and metastasis. Our long-term goal is to identify (and eventually regulate) the molecular mechanisms that promote inactivation of cMet signaling in metastatic pancreatic cancers. Endocytosis is the key pathway for terminating cMet signaling, by targeting the receptor for lysosomal degradation. This project will define the molecular mechanisms that normally regulate cMet internalization and deactivation, and determine whether the endocvtic trafficking of this critical receptor is disrupted in metastatic pancreatic tumors. Our preliminary data show that following activation, cMet is internalized exclusively through clathrin-coated pits. Moreover, cMet internalization and degradation are regulated by distinct subsets of signaling molecules downstream of cMet activation. Our preliminary data also show that cMet degradation is impaired in a metastatic pancreatic adenocarcinoma. We hypothesize that in addition to their established roles in regulating cMet signaling, these signaling molecules link activated cMet to the clathrin-dependent endocvtic machinery for internalization, and that dysregulated cMet internalization and/or degradation could contribute to persistent cMet signaling in certain pancreatic metastases. Our project will test these hypotheses by defining the cMet internalization step(s) regulated by these signaling molecules (Aim 1); delineate the signaling mechanisms downstream of receptor activation that are essential for cMet internalization (Aim 2); and determine which components of the endocytic machinery are modified in response to cMet activation (Aim 3). Finally, we will examine if a common lesion or multiple defects in cMet endocytic trafficking contribute to increased receptor levels and signaling in metastatic pancreatic tumor cells (Aim 4). Pancreatic cancer is a devastating disease, with a 5-year survival rate below 5% due to its high metastatic tendency, difficult early detection, and resistance to conventional treatments. Novel therapeutic strategies are thus urgently needed. Our approach would be to inactivate cMet signaling in tumor cells by inducing receptor endocytosis and inactivation. Our project is novel in that it should elucidate the molecular mechanisms involved in deactivating cMet signaling and how they are dysregulated in pancreatic cancers, an essential prerequisite for designing therapeutic agents targeting pancreatic cancers in which sustained cMet signaling facilitates metastasis.

描述（由申请人提供）：肝细胞生长因子受体（CMET）是对正常细胞反应（例如细胞生长，生存和运动性）至关重要的受体酪氨酸激酶。通常，CMET信号受到严格调节。然而，在包括胰腺癌在内的许多癌症中，CMET信号传导增加发生在许多癌症中，与早期侵袭，传播和转移密切相关。我们的长期目标是确定（并最终调节）促进转移性胰腺癌中CMET信号传导失活的分子机制。内吞作用是靶向溶酶体降解的受体终止CMET信号传导的关键途径。该项目将定义通常调节CMET内部化和失活的分子机制，并确定在转移性胰腺肿瘤中是否会破坏该关键受体的内伏运输。我们的初步数据表明，激活后，CMET仅通过涂有网状蛋白涂层的凹坑进行内部化。此外，CMET内在化和降解受CMET激活下游的信号分子的不同子集调节。我们的初步数据还表明，CMET降解在转移性胰腺腺癌中受损。我们假设，除了它们在调节CMET信号传导中的确定作用外，这些信号分子还将激活的CMET与依赖性的CMET连接到内在化的内部化机制，并且CMEM内部化和/或降解可能有助于某些胰岛酸化的CMET信号传导。我们的项目将通过定义由这些信号分子调节的CMET内部化步骤来检验这些假设（AIM 1）；描述受体激活下游的信号传导机制对于CMET内在化至关重要（AIM 2）；并确定根据CMET激活的响应（AIM 3）修改内吞机械的哪些组件。最后，我们将检查CMET内吞运输中的常见病变或多个缺陷是否有助于转移性胰腺肿瘤细胞的受体水平和信号的增加（AIM 4）。胰腺癌是一种毁灭性的疾病，由于其高转移趋势，难以早期检测和对常规治疗的抵抗力，其存活率低于5％。因此，迫切需要新颖的治疗策略。我们的方法是通过诱导受体内吞和失活来使肿瘤细胞中的CMET信号传导失活。我们的项目是新颖的，因为它应该阐明与CMET信号失活有关的分子机制，以及它们在胰腺癌中的失调，这是设计靶向胰腺癌的治疗剂的必不可少的先决条件，其中持续的CMET信号在其中持续的CMET信号促进了转移。