Role of leukocyte specific adaptor protein leupaxin in T cell migration

白细胞特异性接头蛋白 leupaxin 在 T 细胞迁移中的作用

• 批准号: 13670317
• 负责人: TANAKA Toshiyuki
• 金额: $ 2.11万
• 依托单位: Osaka University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13670317/
• 关键词: leupaxin; paxillin; rote in; tyrosine phosphorylation; focal contact; cell adhesion; cell migration; signal transduction

Although the adhesion and locomotion of leukocytes largely depend on integrins, leukocytes often lack the distinguishable focal adhesions (FAs) that serve as signaling centers in other adherent cells. The assembly and disassembly of FAs is regulated by locally produced intracellular signals, and tyrosine phosphorylation of paxillin has been implicated in this process. Aleukocyte-specific adaptor protein, leupaxin, is a member of the paxillin family and shares overall structural characteristics with paxillin. Leupaxin is composed of multiple functional trbodules, including LD motifs and LIM domains, suggesting that leupaxin also serves as a molecular adaptor that is involved in integrinmediated signaling. However, it remains unknown whether leupaxin and paxillin cooperate with or antagonize each other in integrin signaling. We found that leupaxin potently represses the tyrosine phosphorylation of paxillin. When expressed in mouse thymoma BW5147 cells bound to ICAM-1, leupaxin accumulate … More d in FA like patches in the cell periphery In BW5147 cells migrating on ICAM-1, leupaxin is selectively located at the trailing edge. When expressed in NIH3T3 and HEK293Tcells, leupaxin localized to FAs upon cell adhesion to fibronectin and strongly suppressed the integrin-induced tyrosine phosphorylation of paxillin. In integrin-stimulatecd HEK293Tcells, leupaxin's LIM3 domain appeared essential for the selective FA localization and the suppression of paxillin tyrosine phosphorylation. Leupaxin's LD3 motif, which is critical for stable association with FAK, was dispensable for leupaxin's suppressive ability. In addition, leupaxin reduced the spreading of NIH3T3 cells on fibronectin, which required both the LD3 motif and LIM3 domain. When expressed in human leukocytic K562 cells, leupaxin significantly suppressed integrin α5β1-mediated cell adhesion to fibronectin and the tyrosine phosphorylation of paxillin. These findings indicate that leupaxin functions as a leukocyte-specific counterpart that potently suppresses the tyrosine phosphorylarion of paxillin during integrin signaling Less

虽然白细胞的粘附和运动在很大程度上依赖于整合素，但白细胞通常缺乏可区分的粘着斑（FA），这些粘着斑在其他粘附细胞中充当信号中心。FA的组装和分解受局部产生的细胞内信号调节，桩蛋白的酪氨酸磷酸化参与了这一过程。白浆细胞特异性衔接蛋白leupaxin是桩蛋白家族的成员，与桩蛋白具有相同的结构特征。Leupaxin由多个功能性结构域组成，包括LD基序和LIM结构域，表明Leupaxin也作为分子衔接子参与整合素介导的信号传导。然而，它仍然是未知的亮帕辛和桩蛋白是否相互合作或拮抗整合素信号转导。我们发现leupaxin有效地抑制桩蛋白的酪氨酸磷酸化。当在小鼠胸腺瘤BW 5147细胞中表达时，leupaxin与ICAM-1结合， ...更多信息 d在细胞周边的FA样斑块中在ICAM-1上迁移的BW 5147细胞中，亮帕素选择性地位于后缘。当在NIH 3 T3和HEK 293 T细胞中表达时，leupaxin定位于细胞粘附到纤连蛋白后的FA，并强烈抑制整合素诱导的桩蛋白酪氨酸磷酸化。在整合素刺激的HEK 293 T细胞中，leupaxin的LIM 3结构域对于选择性FA定位和抑制桩蛋白酪氨酸磷酸化是必需的。Leupaxin的LD 3基序对于与FAK的稳定结合至关重要，其对于Leupaxin的抑制能力是不确定的。此外，leupaxin减少了NIH 3 T3细胞在纤连蛋白上的铺展，这需要LD 3基序和LIM 3结构域。当在人白细胞K562细胞中表达时，leupaxin显著抑制整合素α5β1介导的细胞与纤连蛋白的粘附和桩蛋白的酪氨酸磷酸化。这些发现表明leupaxin作为一种白细胞特异性的对应物，在整合素信号传导过程中有效地抑制桩蛋白的酪氨酸磷酸化。

项目成果

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Kimura, F, Gotoh, M., Tanaka, T., Luo, Z., Miyazaki, J., Uede, T., Monden, M., Miyasaka, M.：“胰腺 β 细胞中局部表达的 CTLA4-Ig

Murata, S., et al.: "Lymphocyte binding to MAdCAM-1 via α4β7 integrin activates a signal transduction pathway involving tyrosine phosphorylation of paxillin and p105^<Cas-L>."Immunology Letters. 81. 223-228 (2002)

Murata, S., 等人：“淋巴细胞通过 α4β7 整合素与 MAdCAM-1 结合，激活涉及桩蛋白和 p105^<Cas-L> 酪氨酸磷酸化的信号转导途径。”免疫学快报 81. 223-228 (2002)。

Takeuchi, E et al.: "VLA-4-dependent and -independent pathways in cell contact-induced proinflammatory cytokine production by synovial nurse-like cells from rheumatoid arthritis patients"Arthritis Research. 4. R10 (2002)

Takeuchi, E 等人：“类风湿性关节炎患者的滑膜护士样细胞在细胞接触诱导的促炎细胞因子产生中的 VLA-4 依赖和独立途径”关节炎研究。

Lee, C.M.et al.: "Novel chondroitin sulfate-binding cationic liposomes loaded with cisplatin efficiently suppress the local growth and liver metastasis of tumor cells in vivo"Cancer Research. 62. 4282-4288 (2002)

Lee, C.M.等人：“负载顺铂的新型硫酸软骨素结合阳离子脂质体可有效抑制体内肿瘤细胞的局部生长和肝转移”癌症研究。

Murata, S., Tanaka, T., Miyasaka, M.: "Lymphocyte binding to MAdCAM-1 via a4b7 integrin activates a signal transduction pathway involving tyrosine phosphorylation of paxillin and p105^<Cas-L>"Immnology Letters. 81. 223-228 (2002)

Murata, S.、Tanaka, T.、Miyasaka, M.：“淋巴细胞通过 a4b7 整合素与 MAdCAM-1 结合，激活涉及桩蛋白和 p105^<Cas-L> 酪氨酸磷酸化的信号转导途径”《免疫学快报》。