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

缺乏激酶结构域的截短的Trk受体亚型在发育过程中和成人中大量表达;然而，它们的功能和信号传导能力在很大程度上是未知的。有趣的是，神经营养因子-3（NT 3）截短的TrkCT 1受体的胞质尾在物种间高度保守，表明其在体内具有重要功能的潜力。我们最近发现NT 3与TrkCT 1的相互作用通过支架蛋白Tamalin激活Arf 6-Rac 1信号传导。我们发现TrkCT 1也结合Tamalin同系物Cybr，这是一种在免疫系统中高度表达的支架蛋白。NT 3处理内源性表达TrkCT 1和Cybr的EL 4淋巴瘤细胞系，诱导Cybr的细胞内再定位。由于Cybr参与促炎性酪氨酸调节的细胞迁移，我们的研究结果表明，TrkCT 1可能调节特定白细胞群的招募和迁移。事实上，在我们已经删除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异性缺陷。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，并且患有无菌性腹膜炎的Cybr缺陷小鼠的腹膜腔中存在的细胞比对照组少，并且离开血流的白细胞更少。注射Moloney-鼠肉瘤/白血病病毒的突变小鼠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，特别是在应激条件下对促炎性细胞因子的反应中。我们现在正在研究这些Cybr功能中的哪些受到NT-3/TrkC.T1的影响。在一个单独的项目中，我们研究了Trk受体是否在星形细胞瘤和外周神经薄片瘤（PNST）中表达，这些肿瘤来自缺乏1型神经纤维瘤病和p53基因的小鼠模型。我们发现，截断TrkB（TrkB.T1），神经营养蛋白脑源性神经营养因子（BDNF）的受体表达在所有PNST检查。我们现在正试图确定这种受体亚型在这种类型的肿瘤中的功能，并研究靶向TrkB. T1是否影响肿瘤的存活/生长。

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.