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: 15370056
• 负责人: OKADA Masato
• 金额: $ 9.73万
• 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: 2003
• 资助国家: 日本
• 起止时间: 2003 至 2004
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15370056/
• 关键词: tyrosine kinase; multicellular animal; Src; sponge; choanoflagellate; C.elegans; evolution; 神経幹細胞; 神経系; 卵巣; Csk

Evolution from unicellular protists to mulicellular animals is a crucial event in animal history. To address the molecular events occurred at this transition, we examined the functional alteration of Src tyrosine kinase, as a key molecular switch involved in the animal multicellularity. Orthologues of Src and its negative regulator Csk were molecular cloned from the unicellular choanoflagellate Monosiga ovata and the primitive multicellular sponge Ephydatia fluviatilis, and their activities and regulatory features were comparatively analyzed. Both organisms contain multiple forms of Src with all the domains involved in negative regulation and a functional Csk. In E.fluviatilis, multiple Src isoforms are stringently inhibited by Csk phosphorylation as in vertebrate. However, in M.ovata, Src retains robust activity even in the Csk phosphorylated form, due to deviations in the tertiary structure of the kinase domain. Inhibition of Src in choanoflagellates by the Src inhibitor promotes pol … More arized colony formation mediated by filopodia-like structures. These findings demonstrate that the appearance of Src and its regulatory components predates animal origins, but the regulatory system underwent a functional evolution accompanying the evolution of multicellularity.To address the fundamental roles Src in the multicellular animals, Effects of loss-of-function of Src in C.elegans was analyzed. A mutation in the src-1 gene resulted in defective distal tip cell (DTC)-directed gonad morphogenesis in an activity dependent manner. The effect of the src-1 mutation was robustly suppressed by mutations in the genes located in a Rac pathway, which suggests that SRC-1 is an upstream regulator of the Rac pathway that controls cytoskeletal remodeling. The src-1 mutant also exhibits defects in neural cell migration. These findings suggest that SRC-1 plays an integral role in responding to the extracellular guidance cues that direct the cell migration occurring during development via a pathway that controls cytoskeletal remodeling. Less

从单细胞生物到Muliellular动物的进化是动物史上的关键事件。为了解决该过渡时发生的分子事件，我们研究了SRC酪氨酸激酶的功能改变，作为动物多细胞性的关键分子开关。 SRC及其阴性调节剂CSK的直系同源物是从单细胞Choanoflagellate Monosiga ovata和原始多细胞发起人ephydatia fluviatilis的分子克隆的，并且它们的活性和调节特征是相当分析的。这两种生物都包含多种形式的SRC，其中所有涉及负调控和功能性CSK的域。在大氟维氏菌中，CSK磷酸化严格抑制多种SRC同工型，如脊椎动物中。然而，在M.Ovata中，由于激酶结构域的三级结构的出发，SRC即使在CSK磷酸化形式中也保留了强大的活性。 SRC抑制剂对SRC抑制src促进了POL…由丝状结构介导的更良好的菌落形成。这些发现表明，SRC及其调节成分的外观早于动物起源，但是调节系统经历了多细胞性的功能进化。要解决C.Elegans在C.Elegans中SRC功能丧失的多细胞动物中的基本角色SRC。 SRC-1基因中的突变导致有缺陷的圆盘尖端细胞（DTC）指导的性腺形态发生，以活性依赖性方式。 SRC-1突变的效果通过位于RAC途径中的基因中的突变强抑制，这表明SRC-1是控制细胞骨架重塑的RAC途径的上游调节剂。 SRC-1突变体还表现出神经细胞迁移的缺陷。这些发现表明，SRC-1在响应细胞外引导线索中起着指导细胞迁​​移在发育期间通过控制细胞骨架重塑的途径的作用。较少的

项目成果

Nada S.: "Identification of PSD-93 as substrate for the Src family tyrosine kinase Fyn"J.Biol.Chem.. 278(48). 47610-47621 (2003)

Nada S.：“鉴定 PSD-93 作为 Src 家族酪氨酸激酶 Fyn 的底物”J.Biol.Chem.. 278(48)。

Shima T.: "Transmembrane Phosphoprotein Cbp senses cell adhesion signaling mediated by the Src family kinase in lipid rafts"PNAS.. 100(25). 14897-14902 (2003)

Shima T.：“跨膜磷蛋白 Cbp 感知脂筏中 Src 家族激酶介导的细胞粘附信号传导”PNAS.. 100(25)。

Csk defines the ability of integrin-mediated cell adhesion and migration in human colon cancer cells

Csk 定义了人类结肠癌细胞中整合素介导的细胞粘附和迁移的能力

• 发表时间: 2004
• 期刊: Oncogene 23
• 作者: Mimuro;M.;S.Akimoto;Rengifo-Cam W
• 通讯作者: Rengifo-Cam W

Matsuoka H.: "Mechanism of Csk-mediated down regulation of Src family tyrosine kinases in EGF signaling"J.Biol.Chem.. 279(7). 5975-5983 (2004)

Matsuoka H.：“EGF 信号传导中 Csk 介导的 Src 家族酪氨酸激酶下调机制”J.Biol.Chem.. 279(7)。

Mechanism of Csk-mediated down regulation of Src family tyrosine kinases in EGF signaling.

EGF 信号传导中 Csk 介导的 Src 家族酪氨酸激酶下调机制。

• 发表时间: 2004
• 期刊: J.Biol.Chem. 279
• 作者: Mimuro;M.;H.Kikuchi;Matsuoka H
• 通讯作者: Matsuoka H