Regulation of cell migration and signaling by phosphotyrosine and ubiquitin

磷酸酪氨酸和泛素对细胞迁移和信号传导的调节

基本信息

批准号：
9067447
负责人：
Jonathan A Cooper
金额：
$ 33.81万
依托单位：
FRED HUTCHINSON CANCER RESEARCH CENTER
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-08-01 至 2018-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9067447
关键词：
Address BCAR1 gene Binding Proteins CISH gene Cell Communication Cell Proliferation Cells Cellular biology Complex Cullin 5 Protein Epithelial Cells Epithelium Family Fibroblasts Figs - dietary Focal Adhesions Genes Health Human Immigration Immunity Individual Lead Ligase Link Malignant Neoplasms Mitogens Modeling Molecular Morphology Neurons Phosphorylation Phosphotyrosine Post-Translational Protein Processing Prevalence Protein Dephosphorylation Protein Tyrosine Phosphatase Proteins Regulation Research Role Signal Transduction System Techniques Testing Tumor Suppressor Proteins Tyrosine Phosphorylation Ubiquitin Work Wound Healing adhesion receptor cancer cell cell motility cell transformation cell type in vitro Assay inhibitor/antagonist migration multicatalytic endopeptidase complex novel protein degradation protein protein interaction src-Family Kinases ubiquitin ligase ubiquitin-protein ligase

项目摘要

DESCRIPTION (provided by applicant): Cell migration is regulated by signals from cell-cell interactions, cell-matrix interactions and chemo-attractants and -repellants. Such signals are transduced and coordinated by cascades of post-translational modifications and protein-protein interactions. Specifically, Src family tyrosine kinases are activated by mitogens and adhesion receptors and phosphorylate proteins that organize the leading edge and focal adhesions in migrating cells. The Cullin 5 RING (CRL5) E3 ubiquitin ligase and SOCS proteins (phosphotyrosine-dependent substrate adaptors for CRL5) have been implicated as potential tumor suppressors. We have found that SOCS-CRL5 complexes regulate Src activity, cell migration, proliferation and/or transformation in several cell types. Inhibiting the expression of SOCS proteins or Cul5 in epithelial cells stimulates migration, proliferation, and Src kinase activity. Increased Src is necessary but not sufficient for the increased migration and proliferation of CRL5-deficient cells, suggesting that SOCS-CRL5 complexes have additional substrates. We propose three broad aims to understand in depth how CRL5 regulates Src and cell migration. First, we will determine how CRL5 regulates Src activity. Second, we will identify CRL5 substrates, focusing on those that contain phosphotyrosine, and test which substrates regulate cell migration and proliferation. Third, we will dissect the mechanisms by which SOCS proteins and substrates coordinate focal adhesion and leading edge dynamics during cell migration. Collectively, our research will show how protein-tyrosine phosphorylation and ubiquitylation cooperate to regulate cell biology.

描述（由申请人提供）：细胞迁移受细胞相互作用，细胞 - 矩阵相互作用，化学吸引者和re纤维体的信号调节。通过翻译后修饰和蛋白质 - 蛋白质相互作用的级联反应和协调这样的信号。具体而言，SRC家族酪氨酸激酶被有丝分裂的受体和磷酸化蛋白激活，这些蛋白质在迁移细胞中组织了前缘和局灶性粘附。 Cullin 5环（CRL5）E3泛素连接酶和SOCS蛋白（CRL5的磷酸酪氨酸依赖性底物适配器）已被认为是潜在的肿瘤抑制剂。我们发现SOCS-CRL5复合物调节了几种细胞类型的SRC活性，细胞迁移，增殖和/或转化。抑制上皮细胞中SOCS蛋白或CUL5的表达会刺激迁移，增殖和SRC激酶活性。 SRC增加是必要的，但不足以增加CRL5缺陷型细胞的迁移和增殖，这表明SOCS-CRL5复合物具有额外的底物。我们提出三个广泛的目标，以了解CRL5如何调节SRC和细胞迁移。首先，我们将确定CRL5如何调节SRC活性。其次，我们将确定CRL5底物，重点关注那些含有磷酸酪氨酸的底物，并测试哪些底物调节细胞迁移和增殖。第三，我们将剖析SOCS蛋白和底物在细胞迁移过程中协调局灶性粘附和前缘动态的机制。总的来说，我们的研究将表明蛋白质酪氨酸磷酸化和泛素化如何合作调节细胞生物学。