Mechanisms for regulation of cell adhesion and migration

细胞粘附和迁移的调节机制

• 批准号: 7753888
• 负责人: JULIE L KADRMAS
• 金额: $ 28.31万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-01-01 至 2013-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7753888
• 关键词: Actins; Address; Adhesions; Affect; Affinity; Binding; Binding Proteins; Biological Process; CD47 Antigen; Cell Adhesion; Cell Nucleus; Cell membrane; Cells; Cellular Immunity; Complement; Complex; Coupled; Coupling; Cultured Cells; Cytoplasmic Tail; Cytosol; Data; Defect; Deposition; Disease; Disseminated Malignant Neoplasm; Drosophila genus; Embryo; Embryonic Development; Event; Exhibits; Extracellular Matrix; Gene Expression; Goals; Human; Human Pathology; Immune response; Inflammatory; Inflammatory Response; Integrins; LHX1 gene; LIM Domain; LIMS1 gene; Learning; Leucine-Rich Repeat; Location; Malignant - descriptor; Malignant Neoplasms; Mediating; Membrane; Molecular; Molecular Mechanisms of Action; Neoplasm Metastasis; Neurons; Nuclear; Nuclear Export; Nuclear Translocation; Oncogenic; Phenotype; Phosphotransferases; Play; Prevention strategy; Process; Protein Binding; Protein Binding Domain; Proteins; Recruitment Activity; Regulation; Regulatory Pathway; Relative (related person); Research; Role; Scaffolding Protein; Series; Signal Pathway; Signal Transduction; Site; Source; Stimulus; Structure; Therapeutic Intervention; Tissues; Tumor Cell Invasion; Work; Wound Healing; cell motility; cohort; genetic regulatory protein; insight; integrin-linked kinase; interest; leucine-rich repeat protein; migration; mutant; novel; null mutation; public health relevance; ras Oncogene; receptor; research study; scaffold; therapeutic target; tumor; tumor progression

DESCRIPTION (provided by applicant): Regulated cell adhesion and migration are critical for a variety of biological processes including early embryonic development, neuronal path-finding, inflammatory response, wound healing and tissue integrity, cell-mediated immunity, and tumor invasion and metastasis. Integrin trans-membrane receptors are key regulators of cell migration, and act through an intricate assembly of regulatory proteins associated with the integrin cytoplasmic domain, many of which function as molecular scaffolds. The goal of this research is to identify novel regulatory pathways by which scaffolding proteins modulate cell adhesion and migration via regulated binding of protein partners. In previous work, we characterized the LIM domain scaffold PINCH, which is required for integrin-dependent cell adhesion, migration and signaling. PINCH binds with high affinity to both Integrin-linked kinase (ILK) and Ras suppressor 1 (RSU1), a Leucine-rich repeat protein that suppresses transformation of cultured cells expressing activated Ras, an oncogene present in 30% of all human tumors. We propose that the PINCH scaffold serves as a node for modulating integrin signaling by regulated recruitment of partners like ILK and RSU1, coupled to other signaling pathways. Through a series of experiments in Drosophila in which we specifically disrupt binding interactions with PINCH and alter the subcellular localization of components of the PINCH complex, we will dissect the requirement for ILK and RSU1 binding in carrying out the integrin-dependent functions of PINCH. Our preliminary data indicates that binding to ILK localizes PINCH within integrin-associated complexes at the cell membrane, and regulates the shuttling of PINCH to the nucleus. We will determine if PINCH has essential functions in the nucleus, and whether it has an overlapping complement of binding partners in the cytosol versus the nucleus. Additional data suggest that RSU1 is sequestered in integrin-associated complexes by its interaction with PINCH. We will examine how PINCH-RSU1 binding is regulated, and identify partners and activities for RSU1 that are independent of PINCH. A molecular understanding of how PINCH regulates cell adhesion and migration through its scaffolding activity may ultimately suggest strategies for prevention and therapeutic intervention in human pathologies like metastatic cancer, in which aberrant cell migration plays a prominent role. Public Health Relevance: Cell adhesion and migration are critical components of many biological processes including embryonic development, inflammatory and immune response, wound healing, and tumor invasion and metastasis. Cell adhesion and migration are controlled by an intricate network of regulatory circuits. This research will define new molecular mechanisms by which protein interactions regulate adhesion and migration, with the ultimate goal of identifying potential therapeutic targets for diseases arising from aberrant cell migration, such as the malignant progression of tumors.

描述（由申请人提供）：调节的细胞粘附和迁移对于多种生物学过程至关重要，包括早期胚胎发育、神经元寻路、炎症反应、伤口愈合和组织完整性、细胞介导的免疫以及肿瘤侵袭和转移。整联蛋白跨膜受体是细胞迁移的关键调节因子，并通过与整联蛋白胞质结构域相关的调节蛋白的复杂组装起作用，其中许多调节蛋白作为分子支架起作用。本研究的目的是确定新的调节途径，通过这些途径，支架蛋白通过调节蛋白质伴侣的结合来调节细胞粘附和迁移。在以前的工作中，我们表征了LIM结构域支架PINCH，其是整合素依赖性细胞粘附、迁移和信号传导所需的。PINCH以高亲和力结合整合素连接激酶（ILK）和Ras抑制因子1（RSU 1），RSU 1是一种富含亮氨酸的重复蛋白，可抑制表达活化Ras的培养细胞的转化，Ras是一种存在于30%的人类肿瘤中的癌基因。我们提出PINCH支架作为一个节点，通过调控ILK和RSU 1等伴侣的募集来调节整合素信号传导，并与其他信号传导途径偶联。通过一系列的实验，在果蝇中，我们专门破坏与PINCH结合的相互作用，并改变亚细胞定位的PINCH复合物的组成部分，我们将剖析的要求ILK和RSU 1结合在进行整合素依赖的功能PINCH。我们的初步数据表明，结合ILK定位PINCH内整合素相关的复合物在细胞膜上，并调节穿梭的PINCH的细胞核。我们将确定PINCH是否在细胞核中具有重要功能，以及它是否在细胞质中与细胞核中具有重叠的结合伴侣。额外的数据表明，RSU 1通过其与PINCH的相互作用被隔离在整合素相关复合物中。我们将研究如何PINCH-RSU 1绑定的监管，并确定合作伙伴和活动RSU 1是独立的PINCH。对PINCH如何通过其支架活性调节细胞粘附和迁移的分子理解可能最终为预防和治疗性干预人类病理学（如转移性癌症）提供策略，其中异常细胞迁移起着重要作用。公共卫生相关性：细胞粘附和迁移是许多生物学过程的关键组成部分，包括胚胎发育、炎症和免疫反应、伤口愈合以及肿瘤侵袭和转移。细胞粘附和迁移是由一个复杂的调控网络控制的。这项研究将确定蛋白质相互作用调节粘附和迁移的新分子机制，最终目标是确定异常细胞迁移引起的疾病的潜在治疗靶点，例如肿瘤的恶性进展。