Role of tyrosine kinase in the evolution of multicellular animals

酪氨酸激酶在多细胞动物进化中的作用

• 批准号: 17370048
• 负责人: OKADA Masato
• 金额: $ 9.47万
• 依托单位: Osaka University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2005
• 资助国家: 日本
• 起止时间: 2005 至 2006
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-17370048/
• 关键词: tyrosine kinase; multicellular animal; Src; sponge; choanoflagellate; C.elegans; evolution; Csk; 線虫

The Src family of tyrosine kinases play pivotal roles in regulating cellular functions characteristic of multicellular animals, including cell-cell interactions, cell-substrate adhesion and cell migration. To investigate the functional alteration of Src kinases during evolution from a unicellular ancestor to multicellular animals, we characterized Src orthologs from the unicellular choanoflagellate Monosiga ovata and the primitive multicellular sponge Ephydatia fluviatilis. Here, we show that the src gene family and its C-terminal Src kinase (Csk)-mediated regulatory system were already established in the unicellular M.ovata and that this Src has unique features relative to multicellular Src : it can be phosphorylated by Csk at the negative regulatory site, but still exhibits substantial activity even in the phosphorylated form. Analyses of chimera molecules between M.ovata and E. fluviatilis Src orthologs reveal that structural alterations in the kinase domain are responsible for the … More inefficient negative regulation of M.ovata Src. When expressed in vertebrate fibroblasts, M.ovata Src can induce cell transformation irrespective of the presence of Csk. These findings suggest that a structure of Src required for the stable Csk-mediated negative regulation is still immature in the unicellular M.ovata, and that the development of stable negative regulation of Src may correlate with the evolution of multicellularity in animals.To address the fundamental roles Src in the multicellular animals, Effects of loss-of-function of Src in C.elegans was analyzed. Here we show that SRC-1, an orthologue of SFK, plays an essential role in directing cell migration in Caenorhabditis elegans. The mutation in the src-l gene results in defective distal tip cell (DTC)-directed gonad morphogenesis in an activity-dependent and DTC cell-autonomous manners. In the src-1 mutants, DTCs fail to turn and continue their centrifugal migration along the ventral muscles. The effect of the src-l mutation is suppressed by mutations in genes that function in the CED/Rac pathway, suggesting that SRC-1 in DTCs is an upstream regulator of a Rac pathway that controls cytoskeletal remodeling. In the src-1 mutant, the expression of unc-5/netrin receptor is normally regulated, and either the precocious expression of UNC-5 or the mutation in the unc-5 gene does not significantly affect the DTC migration defect. These data suggest that SRC-1 acts in the netrin signaling in DTCs. The src-1 mutant also exhibits cell-autonomous defects in the migration and growth cone path finding of Q neuroblast descendants AVM and PVM. However, these roles of SRC-1 do not appear to involve the CED/Rac pathway. These findings show that SRC-1 functions in responding to various extracellular guidance cues that direct the cell migration via disparate signaling pathways in different cell types. Less

酪氨酸激酶的 Src 家族在调节多细胞动物的细胞功能特征中发挥着关键作用，包括细胞与细胞的相互作用、细胞与基质的粘附以及研究从单细胞祖先到多细胞动物的进化过程中 Src 激酶的功能改变。我们鉴定了单细胞领鞭毛虫 Monosiga ovata 和原始多细胞海绵 Ephydatiia Fluviatilis 的 Src 直系同源物。在这里，我们展示了 src 基因家族。其C端Src激酶（Csk）介导的调节系统已经在单细胞M.ovata中建立，并且该Src相对于多细胞Src具有独特的特征：它可以在负调节位点被Csk磷酸化，但仍然表现出对 M.ovata 和 E.fluviatilis Src 直向同源物之间的嵌合分子的分析表明，激酶结构域的结构改变是导致……更多M.ovata Src 的低效负调节。当在脊椎动物成纤维细胞中表达时，无论 Csk 是否存在，M.ovata Src 都可以诱导细胞转化。这些发现表明，稳定的 Csk 介导的负调节所需的 Src 结构仍不成熟。在单细胞 M.ovata 中，Src 稳定负调节的发展可能与动物多细胞性的进化相关。为了解决 Src 在多细胞动物中的基本作用，在这里，我们分析了 Src 在秀丽隐杆线虫中的功能丧失，表明 SFK 的直系同源物 SRC-1 在指导秀丽隐杆线虫中的细胞迁移中起着重要作用。 src-1 基因的突变导致缺陷。在 src-1 突变体中，远端尖端细胞（DTC）以活性依赖性和 DTC 细胞自主的方式指导性腺形态发生。旋转并继续沿着腹侧肌肉进行离心迁移。 src-1 突变的作用被 CED/Rac 通路中起作用的基因突变所抑制，这表明 DTC 中的 SRC-1 是 Rac 通路的上游调节因子。在 src-1 突变体中，unc-5/netrin 受体的表达受到正常调节，并且 UNC-5 的早熟表达或 unc-5 中的突变。这些数据表明，SRC-1 在 DTC 的 netrin 信号传导中发挥作用，src-1 突变体在 Q 神经母细胞后代 AVM 和生长锥路径寻找中也表现出细胞自主缺陷。然而，SRC-1 的这些作用似乎并不涉及 CED/Rac 通路。这些发现表明，SRC-1 的功能是通过不同的细胞外引导信号来指导细胞迁​​移。不同细胞类型的信号通路较少。

项目成果

Crystallization and preliminary X-ray analysis of rat SHPS-1.

大鼠 SHPS-1 的结晶和初步 X 射线分析。

• 发表时间: 2006
• 期刊: Acta Crystallograph Sect F Struct Biol Cryst Commun. 62
• 作者: Nagata A;Ohnishi H;Yoshimura M;Ogawa A;Ujita S;Adachi H;Okada M;Matozaki T;Nakagawa A.
• 通讯作者: Nakagawa A.

Targeting AMAP1 and cortactin binding bearing an atypical src homology 3/proline interface for prevention of breast cancer invasion and metastasis.

靶向具有非典型 src 同源 3/脯氨酸界面的 AMAP1 和 cortactin 结合，用于预防乳腺癌侵袭和转移。

• 发表时间: 2006
• 期刊: Proc Natl Acad Sci U S A. 103
• 作者: Hashimoto S;Hirose M;Hashimoto A;Morishige M;Yamada A;Hosaka H;Akagi K;Ogawa E;Oneyama C;Agatsuma T;Okada M;Kobayashi H;Wada H;Nakano H;Ikegami T;Nakagawa A;Sabe H.
• 通讯作者: Sabe H.

Potentiation of the ligand-binding activity of integrin alpha3beta1 via association with tetraspanin CD151.

通过与四跨膜蛋白 CD151 结合增强整合素 α3β1 的配体结合活性。

• 发表时间: 2005
• 期刊: Proc Natl Acad Sci USA 102・6
• 作者: Kasai A;Shima T;Okada M.;Nishiuchi R.
• 通讯作者: Nishiuchi R.

Crystallization and preliminary X-ray analysis of rat SHPS-1

大鼠 SHPS-1 的结晶和初步 X 射线分析

• 发表时间: 2006
• 期刊: Crystallograph Sect F Struct Biol Cryst Commun. 1;62(Pt 3)
• 作者: Azuma H;Ehata S;Miyazaki H;Watabe T;Miyazono K. et al.;Nagata A
• 通讯作者: Nagata A