Role of Synaptojanin 2 in Tumor Cell Invasion

描述（由申请人提供）：肿瘤细胞的迁移和侵袭特性对于转移至关重要，转移是癌症患者治疗失败的主要原因。然而，控制细胞迁移和侵袭的信号机制在很大程度上仍有待阐明。该提案的长期目标是阐明在控制细胞迁移和侵袭中由小GTCRac 1激活的信号通路，并利用这些信息来确定癌症治疗的新药物靶点。磷脂酰肌醇磷酸酶synaptojanin 2（SJ 2）是一种新的Rac效应物，其是形成片状伪足和侵入伪足以及肿瘤细胞迁移和侵袭所需的。此外，SJ 2与Grb 2和corbrin结合，这两种蛋白质参与了肌动蛋白细胞骨架的控制。Grb 2激活N-WASP，其刺激肌动蛋白成核，而corbrin促进肌动蛋白丝分支形成。本申请的目的是确定SJ 2在板状伪足和侵袭伪足形成以及肿瘤细胞迁移和侵袭中的作用的分子机制。该提议的中心假设是SJ 2通过在Rac 1下游起作用以协调N-WASP和corpine的活性而促进肿瘤细胞迁移和侵袭。为了实现本申请的目标，将追求以下具体目标：1）确定Rac 1是否通过将SJ 2定位于板状伪足和侵袭伪足来调节SJ 2。2)验证SJ 2通过刺激皮质素依赖的肌动蛋白丝分支来调节细胞迁移和侵袭以及板状伪足和侵袭伪足的形成的假设。3)验证synaptojanin 2通过调节Grb 2/N-WASP依赖的肌动蛋白成核来调节细胞迁移和侵袭以及板状伪足和侵袭伪足的形成的假说。对SJ 2在板状伪足和侵袭伪足的形成以及肿瘤细胞迁移和侵袭中的功能的分子分析将显著扩展我们目前对Rac 1在恶性转化中的作用的理解。

DESCRIPTION (provided by applicant): The migratory and invasive properties of tumor cells are critical for metastasis, which is the main cause of treatment failure for cancer patients. The signaling mechanisms that control cell migration and invasion largely remain to be elucidated however. The long-term goal of this proposal is to elucidate the signaling pathways that are activated by the small GTPase Rac1 in the control of cell migration and invasion and to use this information to identify novel drug targets for cancer therapy. The phosphatidylinositol phosphatase synaptojanin 2 (SJ2) is a novel Rac effector that is required for the formation of lamellipodia and invadopodia and for tumor cell migration and invasion. Furthermore, SJ2 binds to Grb2 and cortactin, two proteins that have been implicated in the control of the actin cytoskeleton. Grb2 activates N-WASP, which stimulates actin nucleation, whereas cortactin promotes actin filament branch formation. The objective of this application is to determine the molecular mechanisms that underlie the role of SJ2 in lamellipodia and invadopodia formation and tumor cell migration and invasion. The central hypothesis of this proposal is that SJ2 contributes to tumor cell migration and invasion by acting downstream of Rac1 to coordinate the activities of N-WASP and cortactin. To accomplish the goals of this application, the following specific aims will be pursued: 1) To determine whether Rac1 regulates SJ2 by localizing SJ2 to lamellipodia and invadopodia. 2) To test the hypothesis that SJ2 regulates cell migration and invasion and the formation of lamellipodia and invadopodia by stimulating cortactin-dependent actin filament branching. 3) To test the hypothesis that synaptojanin 2 regulates cell migration and invasion and the formation of lamellipodia and invadopodia by regulating Grb2/N-WASP-dependent actin nucleation. The molecular analysis of the functions of SJ2 in the formation of lamellipodia and invadopodia and tumor cell migration and invasion will significantly expand our current understanding of the role of Rac1 in malignant transformation.