Beta1 Integrins and IGF-I Receptor in Prostate Cancer

前列腺癌中的 Beta1 整合素和 IGF-I 受体

基本信息

批准号：
7364211
负责人：
Lucia R. Languino
金额：
$ 27.39万
依托单位：
UNIV OF MASSACHUSETTS MED SCH WORCESTER
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-04-06 至 2010-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7364211
关键词：
1-Phosphatidylinositol 3-Kinase Adhesions Basement membrane Binding CD29 Antigen Cell Adhesion Cell Line Cell Proliferation Cell membrane Cell physiology Cells Complex Cytoplasmic Tail Data ECM receptor Elements Event Experimental Models Extracellular Matrix Proteins Growth Factor Receptors Human In Vitro Individual Insulin-Like Growth Factor Receptor Insulin-Like-Growth Factor I Receptor Integrins Invaded Laminin Malignant neoplasm of prostate Mediating Membrane Proteins Modeling Molecular Mus Neoplastic Cell Transformation PTK2 gene Pathway interactions Phosphoric Monoester Hydrolases Phosphotransferases Play Prostate Prostate Cancer therapy Prostatic Neoplasms Proto-Oncogene Proteins c-akt RNA Splicing Research Personnel Role Signal Pathway Signal Transduction Small Interfering RNA Somatomedins Specimen Staging Testing Therapeutic Tissues Up-Regulation Validation Variant base cancer cell design in vivo insight member mouse model mutant neoplastic neoplastic cell novel prevent programs receptor response tumor tumor growth tumor progression

项目摘要

DESCRIPTION (provided by applicant): Integrins' ability to control cancer cell proliferation, survival and adhesion plays an important role in tumor progression. Recent findings by the PI have unraveled a novel molecular interface between members of the beta1 integrin subfamily and IGF-IR (Insulin-like Growth Factor Receptor), a kinase receptor known to be significantly upregulated in prostate cancer. The PI describes a novel mechanism that controls prostate cancer cell functions and occurs via a selective modulation of IGF-IR signaling by beta1 integrins in response to IGF-stimulation. Through differential recruitment of signaling complexes to their alternatively spliced cytoplasmic domains, the PI found that the association of beta1A with IGF-IR promotes IGF-IR - stimulated cell proliferation and prevents IGF-mediated cell adhesion to basement membrane proteins, thus presumably allowing the tumor mass to expand and invade. In contrast, the beta1C cytoplasmic integrin variant antagonizes these effects, suppresses IGF-IR - stimulated cell proliferation and promotes firm adhesion to basement membrane proteins. The mechanism by which the beta1 integrin cytodomain differentially modulates prostate cancer cell functions in response to IGF occurs via differential recruitment to the plasma membrane of IGF-IR downstream effectors. Consistent with these findings is also the observation that both beta1 and IGF-IR are concurrently upregulated in the early stages of neoplastic transformation in a mouse model of prostate cancer. The hypothesis to be tested in the present application, based on the findings described above, is that beta1 integrins modulate IGF-IR signaling and functions in prostate cancer progression. It is specifically planned, in Aim 1, to dissect in vitro the role of the beta1A-IGF-IR complex and of beta1C in modulating prostate cancer cell functions. In Aim 2, the PI plans to study the localization of the beta1A-IGF-IR complex, the modulation of the activity of the complex by specific substrates as well as the signaling pathways downstream of the beta1A-IGF-IR complex and of beta1C. In Aim 3, the PI will analyze in vivo the role of beta1 integrins and IGF-IR and of the beta1A-IGF-IR complex in prostate cancer progression. This study is designed to elucidate novel molecular interactions between integrins and growth factor receptors in prostate cancer and will allow new target validation in prostate cancer therapy.

描述（由申请人提供）：整合素控制癌细胞增殖、存活和粘附的能力在肿瘤进展中发挥重要作用。 PI 最近的研究结果揭示了 β1 整合素亚家族成员与 IGF-IR（胰岛素样生长因子受体）之间的新型分子界面，IGF-IR 是一种已知在前列腺癌中显着上调的激酶受体。 PI描述了一种控制前列腺癌细胞功能的新机制，该机制是通过β1整合素响应IGF刺激选择性调节IGF-IR信号而发生的。通过将信号复合物差异招募到其选择性剪接的细胞质结构域，PI 发现 beta1A 与 IGF-IR 的结合促进 IGF-IR 刺激的细胞增殖，并阻止 IGF 介导的细胞粘附到基底膜蛋白，从而可能使肿瘤质量扩张和入侵。相反，β1C 细胞质整合素变体可以拮抗这些效应，抑制 IGF-IR 刺激的细胞增殖并促进与基底膜蛋白的牢固粘附。 β1 整联蛋白细胞结构域响应 IGF 差异调节前列腺癌细胞功能的机制是通过差异招募 IGF-IR 下游效应子的质膜而发生的。与这些发现一致的是，在前列腺癌小鼠模型的肿瘤转化早期阶段，β1 和 IGF-IR 同时上调。基于上述发现，本申请中待测试的假设是β1整联蛋白在前列腺癌进展中调节IGF-IR信号传导和功能。目标 1 特别计划在体外剖析 beta1A-IGF-IR 复合物和 beta1C 在调节前列腺癌细胞功能中的作用。在目标 2 中，PI 计划研究 beta1A-IGF-IR 复合物的定位、特定底物对该复合物活性的调节以及 beta1A-IGF-IR 复合物和 beta1C 下游的信号传导途径。在目标 3 中，PI 将在体内分析 β1 整联蛋白和 IGF-IR 以及 β1A-IGF-IR 复合物在前列腺癌进展中的作用。这项研究旨在阐明前列腺癌中整合素和生长因子受体之间的新型分子相互作用，并将为前列腺癌治疗提供新的靶点验证。