Role of Trk Receptors in the Development and Function of Non-neuronal Structures

Trk 受体在非神经元结构发育和功能中的作用

• 批准号: 7965298
• 负责人: Lino Tessarollo
• 金额: $ 58.14万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7965298
• 关键词: Accounting; Address; Adult; Affect; Aggressive behavior; Animal Model; Astrocytoma; Binding; Birth; Blood; Brain; Cell Line; Cell physiology; Cells; Cytoplasmic Tail; Cytotoxic T-Lymphocytes; Data; Development; Enlargement of lymph nodes; Goals; Greater sac of peritoneum; Growth; Homologous Gene; Human; Immune; Immune system; Inflammatory; Inflammatory Response; Intervention; Left; Leukocyte Trafficking; Leukocytes; Lymphocyte; Lymphoma; Malignant Neoplasms; Mediating; Mus; Mutant Strains Mice; Nephroblastoma; Nerve Growth Factor Receptors; Nervous system structure; Neuroblastoma; Neurofibromatosis 1; Neurons; Neurotrophin 3; Pancreas; Peripheral Nerves; Peripheral Nervous System Neoplasms; Peritonitis; Phosphotransferases; Population; Prostate carcinoma; Protein Isoforms; Reporting; Role; Scaffolding Protein; Signal Transduction; Stream; Stress; Structure; System; TP53 gene; Wild Type Mouse; cell motility; cytokine; in vivo; leukemia virus; lymph nodes; migration; mouse model; neurotrophic factor; outcome forecast; overexpression; receptor; receptor function; response; sarcoma; trafficking; tumor

Truncated Trk receptor isoforms lacking the kinase domain are abundantly expressed during development and in the adult; however, their function and signaling capacity is largely unknown. Interestingly, the cytoplasmic tail of the neurotrophin-3 (NT3) truncated TrkCT1- receptor is highly conserved among species, suggesting the potential for important functions in vivo. We have recently shown that NT3 interaction with TrkCT1 activates Arf6-Rac1 signaling through the scaffold protein Tamalin. We found that TrkCT1 binds also the Tamalin homolog Cybr, a scaffold protein highly expressed in the immune system. NT3 treatment of the EL4 lymphoma cell line that express endogenously both TrkCT1 and Cybr, induces intracellular re-localization of Cybr. Since Cybr is involved in pro-inflammatory cytokine-modulated cell migration, our results suggest that TrkCT1 may modulate the recruitment and migration of specific leukocyte cell populations. Indeed, in mouse in which we have deleted Cybr we find specific deficits in blood circulating leukocytes and lymphocytes present in the lymph nodes. Moreover, in a Th1-polarized-mouse model, lymphocyte trafficking is impaired by loss of Cybr and Cybr-deficient mice with aseptic peritonitis have fewer cells than controls present in the peritoneal cavity and fewer leukocytes leaving the blood stream. Mutant mice injected with Moloney-murine sarcoma/leukemia virus develop significantly larger tumors than wild type mice and have reduced lymph node enlargement suggesting reduced cytotoxic T lymphocytes migration. Taken together, these data support a role for Cybr in leukocyte trafficking, especially in response to pro-inflammatory cytokines in stress conditions. We are now investigating which of these Cybr functions are affected by NT-3/TrkC.T1. In a separate project we have investigated whether Trk Receptors are expressed in astrocytomas and peripheral nerve sheet tumor (PNST) that develop from a mouse model lacking the neurofibromatosis type 1 and p53 gene. We found that Truncated TrkB (TrkB.T1), a receptor for the neurotrophin brain derived neurotrophin factor (BDNF) is expressed in all PNST examined. We are now trying to identify the function of this receptor isoform in this type of tumors and investigate whether targeting of TrkB.T1affects tumor survival/growth.Truncated Trk receptor isoforms lacking the kinase domain are abundantly expressed during development and in the adult; however, their function and signaling capacity is largely unknown. Interestingly, the cytoplasmic tail of the neurotrophin-3 (NT3) truncated TrkCT1- receptor is highly conserved among species, suggesting the potential for important functions in vivo. We have recently shown that NT3 interaction with TrkCT1 activates Arf6-Rac1 signaling through the scaffold protein Tamalin. We found that TrkCT1 binds also the Tamalin homolog Cybr, a scaffold protein highly expressed in the immune system. NT3 treatment of the EL4 lymphoma cell line that express endogenously both TrkCT1 and Cybr, induces intracellular re-localization of Cybr. Since Cybr is involved in pro-inflammatory cytokine-modulated cell migration, our results suggest that TrkCT1 may modulate the recruitment and migration of specific leukocyte cell populations. Indeed, in mouse in which we have deleted Cybr we find specific deficits in blood circulating leukocytes and lymphocytes present in the lymph nodes. Moreover, in a Th1-polarized-mouse model, lymphocyte trafficking is impaired by loss of Cybr and Cybr-deficient mice with aseptic peritonitis have fewer cells than controls present in the peritoneal cavity and fewer leukocytes leaving the blood stream. Mutant mice injected with Moloney-murine sarcoma/leukemia virus develop significantly larger tumors than wild type mice and have reduced lymph node enlargement suggesting reduced cytotoxic T lymphocytes migration. Taken together, these data support a role for Cybr in leukocyte trafficking, especially in response to pro-inflammatory cytokines in stress conditions. We are now investigating which of these Cybr functions are affected by NT-3/TrkC.T1. In a separate project we have investigated whether Trk Receptors are expressed in astrocytomas and peripheral nerve sheet tumor (PNST) that develop from a mouse model lacking the neurofibromatosis type 1 and p53 gene. We found that Truncated TrkB (TrkB.T1), a receptor for the neurotrophin brain derived neurotrophin factor (BDNF) is expressed in all PNST examined. We are now trying to identify the function of this receptor isoform in this type of tumors and investigate whether targeting of TrkB.T1affects tumor survival/growth.

缺失激活域的Trk受体亚型在发育过程中和成体中大量表达；然而，它们的功能和信号转导能力在很大程度上是未知的。有趣的是，神经营养素-3(NT3)截短的TrkCT1受体的细胞质尾部在物种之间高度保守，表明在体内具有重要功能的潜力。我们最近发现，NT3与TrkCT1的相互作用通过支架蛋白Tamalin激活了Arf6-rac1信号。我们发现TrkCT1还与Tamalin同源CybR结合，这是一种在免疫系统中高度表达的支架蛋白。NT3处理同时内源性表达TrkCT1和Cybr的EL4淋巴瘤细胞系，诱导Cybr在细胞内重新定位。由于CybR参与促炎细胞因子调节的细胞迁移，我们的结果提示TrkCT1可能调节特定白细胞群体的募集和迁移。事实上，在我们删除了CybR的小鼠中，我们发现血液循环中的白细胞和淋巴结内的淋巴细胞存在特定的缺陷。此外，在Th1极化的小鼠模型中，由于Cybr的丢失，淋巴细胞的运输受到损害，Cybr缺陷的无菌性腹膜炎小鼠的腹膜细胞比对照组少，离开血流的白细胞也少。注射Moloney-小鼠肉瘤/白血病病毒的突变小鼠比野生型小鼠发展出显着更大的肿瘤，并减少了淋巴肿大，这表明细胞毒性T淋巴细胞迁移减少。综上所述，这些数据支持CybR在白细胞运输中的作用，特别是在应激条件下对促炎细胞因子的反应。我们现在正在调查这些CybR功能中的哪些会受到NT-3/TrkC.T1的影响。在另一个单独的项目中，我们研究了Trk受体是否在星形细胞瘤和周围神经片状肿瘤(PNST)中表达，这些肿瘤是从缺乏神经纤维瘤病1型和p53基因的小鼠模型发展而来的。我们发现神经营养因子脑源性神经营养因子受体TrkB(TrkB.T1)在所有PNST中都有表达。我们现在正试图确定这种受体亚型在这类肿瘤中的功能，并研究靶向TrkB·T1是否影响肿瘤的存活/生长。缺失激活域的Trk受体亚型在发育过程中和成人中大量表达；然而，它们的功能和信号转导能力在很大程度上是未知的。有趣的是，神经营养素-3(NT3)截短的TrkCT1受体的细胞质尾部在物种之间高度保守，表明在体内具有重要功能的潜力。我们最近发现，NT3与TrkCT1的相互作用通过支架蛋白Tamalin激活了Arf6-rac1信号。我们发现TrkCT1还与Tamalin同源CybR结合，这是一种在免疫系统中高度表达的支架蛋白。NT3处理同时内源性表达TrkCT1和Cybr的EL4淋巴瘤细胞系，诱导Cybr在细胞内重新定位。由于CybR参与促炎细胞因子调节的细胞迁移，我们的结果提示TrkCT1可能调节特定白细胞群体的募集和迁移。事实上，在我们删除了CybR的小鼠中，我们发现血液循环中的白细胞和淋巴结内的淋巴细胞存在特定的缺陷。此外，在Th1极化的小鼠模型中，由于Cybr的丢失，淋巴细胞的运输受到损害，Cybr缺陷的无菌性腹膜炎小鼠的腹膜细胞比对照组少，离开血流的白细胞也少。注射Moloney-小鼠肉瘤/白血病病毒的突变小鼠比野生型小鼠发展出显着更大的肿瘤，并减少了淋巴肿大，这表明细胞毒性T淋巴细胞迁移减少。综上所述，这些数据支持CybR在白细胞运输中的作用，特别是在应激条件下对促炎细胞因子的反应。我们现在正在调查这些CybR功能中的哪些会受到NT-3/TrkC.T1的影响。在另一个单独的项目中，我们研究了Trk受体是否在星形细胞瘤和周围神经片状肿瘤(PNST)中表达，这些肿瘤是从缺乏神经纤维瘤病1型和p53基因的小鼠模型发展而来的。我们发现神经营养因子脑源性神经营养因子受体TrkB(TrkB.T1)在所有PNST中都有表达。我们现在正试图确定这种受体亚型在这类肿瘤中的功能，并研究靶向TrkB.T1是否影响肿瘤的存活/生长。