Role of Synaptojanin 2 in Tumor Cell Invasion

描述（申请人提供）：肿瘤细胞的迁移和侵袭性是转移的关键，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。本研究的长期目标是阐明由小GTPase Rac1激活的控制细胞迁移和侵袭的信号通路，并利用这些信息确定癌症治疗的新药物靶点。磷脂酰肌醇磷酸酶synaptojanin 2 （SJ2）是一种新的Rac效应物，是板足和侵入足形成以及肿瘤细胞迁移和侵袭所必需的。此外，SJ2结合Grb2和皮质蛋白，这两种蛋白与肌动蛋白细胞骨架的控制有关。Grb2激活N-WASP，刺激肌动蛋白成核，而cortnn促进肌动蛋白丝分支的形成。本应用程序的目的是确定SJ2在板足和侵入足形成以及肿瘤细胞迁移和侵袭中作用的分子机制。本研究的中心假设是，SJ2通过在Rac1的下游作用，协调N-WASP和接触蛋白的活性，从而促进肿瘤细胞的迁移和侵袭。为了实现本应用的目标，将追求以下具体目标：1)确定Rac1是否通过将SJ2定位于板足和侵入足来调控SJ2。2)验证SJ2通过刺激接触蛋白依赖的肌动蛋白丝分支，调控细胞迁移和侵袭以及板足和侵入足形成的假说。3)验证synaptojanin 2通过调控Grb2/ n - wasp依赖的肌动蛋白成核，调控细胞迁移、侵袭及板状足和侵入足形成的假说。通过对SJ2在板足和内足形成以及肿瘤细胞迁移和侵袭中的功能的分子分析，将大大扩展我们目前对Rac1在恶性转化中的作用的认识。

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.