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.

缺乏激酶结构域的截短的Trk受体同种型大量表达 在发育过程中和成人;然而，它们的功能和信号能力在很大程度上是 未知有趣的是，神经营养素-3（NT 3）截短的TrkCT 1- 受体在物种间高度保守，表明其具有重要功能的潜力 in vivo.我们最近发现NT 3与TrkCT 1的相互作用激活Arf 6-Rac 1信号传导 通过支架蛋白Tamalin。我们发现TrkCT 1也结合Tamalin同系物， Cybr是一种在免疫系统中高度表达的支架蛋白。NT 3治疗EL 4 内源性表达TrkCT 1和Cybr淋巴瘤细胞系诱导细胞内 Cybr的重新定位由于Cybr参与了促炎性细胞因子调节的细胞凋亡， 迁移，我们的研究结果表明，TrkCT 1可以调节募集和迁移的 特异性白细胞群。事实上，在我们删除Cybr的小鼠中，我们发现 淋巴结中存在的血液循环白细胞和淋巴细胞的特定缺陷。 此外，在Th 1-极化小鼠模型中，淋巴细胞运输因Cybr缺失而受损。 而Cybr缺陷的无菌性腹膜炎小鼠的细胞比对照组少， 腹膜腔和离开血流的白细胞较少。突变小鼠注射 Moloney-鼠肉瘤/白血病病毒比野生型小鼠产生显著更大的肿瘤 并且具有减少的淋巴结肿大，表明细胞毒性T淋巴细胞迁移减少。 总之，这些数据支持Cybr在白细胞运输中的作用，特别是在 在应激条件下对促炎细胞因子的反应。我们正在调查 这些Cybr功能受到NT-3/TrkC.T1的影响。在我们调查的另一个项目中， Trk受体是否在星形细胞瘤和外周神经片瘤（PNST）中表达 这些细胞是从缺乏1型神经纤维瘤病和p53基因的小鼠模型中产生的。我们发现 TrkB（TrkB.T1）是一种神经营养蛋白脑源性神经营养蛋白受体， BDNF在所有检测的PNST中均有表达。我们现在正试图确定 这种受体亚型在这种类型的肿瘤，并研究是否靶向 TrkB.T1影响肿瘤存活/生长。缺乏激酶结构域的截短Trk受体亚型大量表达 在发育过程中和成人;然而，它们的功能和信号能力在很大程度上是 未知有趣的是，神经营养素-3（NT 3）截短的TrkCT 1- 受体在物种间高度保守，表明其具有重要功能的潜力 in vivo.我们最近发现NT 3与TrkCT 1的相互作用激活Arf 6-Rac 1信号传导 通过支架蛋白Tamalin。我们发现TrkCT 1也结合Tamalin同系物， Cybr是一种在免疫系统中高度表达的支架蛋白。NT 3治疗EL 4 内源性表达TrkCT 1和Cybr淋巴瘤细胞系诱导细胞内 Cybr的重新定位由于Cybr参与了促炎性细胞因子调节的细胞凋亡， 迁移，我们的研究结果表明，TrkCT 1可以调节募集和迁移的 特异性白细胞群。事实上，在我们删除Cybr的小鼠中，我们发现 淋巴结中存在的血液循环白细胞和淋巴细胞的特定缺陷。 此外，在Th 1-极化小鼠模型中，淋巴细胞运输因Cybr缺失而受损。 而Cybr缺陷的无菌性腹膜炎小鼠的细胞比对照组少， 腹膜腔和更少的白细胞离开血流。突变小鼠注射 Moloney-鼠肉瘤/白血病病毒比野生型小鼠产生显著更大的肿瘤 并且具有减少的淋巴结肿大，表明细胞毒性T淋巴细胞迁移减少。 总之，这些数据支持Cybr在白细胞运输中的作用，特别是在 在应激条件下对促炎细胞因子的反应。我们正在调查 这些Cybr功能受到NT-3/TrkC.T1的影响。在我们调查的另一个项目中， Trk受体是否在星形细胞瘤和外周神经片瘤（PNST）中表达 这些细胞是从缺乏1型神经纤维瘤病和p53基因的小鼠模型中产生的。我们发现 TrkB（TrkB.T1）是一种神经营养蛋白脑源性神经营养蛋白受体， BDNF在所有检测的PNST中均有表达。我们现在正试图确定 这种受体亚型在这种类型的肿瘤，并研究是否靶向 TrkB.T1影响肿瘤存活/生长。