Beta1 Integrins and IGF-I Receptor in Prostate Cancer

描述（由申请人提供）：整联蛋白控制癌细胞增殖、存活和粘附的能力在肿瘤进展中起重要作用。PI最近的发现揭示了β 1整合素亚家族成员与IGF-IR（胰岛素样生长因子受体）之间的一种新的分子界面，IGF-IR是一种已知在前列腺癌中显著上调的激酶受体。PI描述了一种控制前列腺癌细胞功能的新机制，并通过β 1整合素对IGF-刺激的反应选择性调节IGF-IR信号传导而发生。通过将信号复合物差异募集到其可变剪接的胞质结构域，PI发现β 1A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，从而可能允许肿瘤块扩张和侵袭。相反，β 1C胞质整合素变体拮抗这些作用，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。β 1整联蛋白胞内结构域响应IGF差异调节前列腺癌细胞功能的机制是通过IGF-IR下游效应物向质膜的差异募集而发生的。与这些发现一致的是，在小鼠前列腺癌模型中，β 1和IGF-IR在肿瘤转化的早期阶段同时上调。基于上述发现，本申请中待检验的假设是β 1整联蛋白调节IGF-IR信号传导和在前列腺癌进展中的功能。在目的1中，特别计划在体外剖析β 1A-IGF-IR复合物和β 1C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β 1A-IGF-IR复合物的定位、特定底物对复合物活性的调节以及β 1A-IGF-IR复合物和β 1C下游的信号传导途径。在目标3中，PI将在体内分析β 1整合素和IGF-IR以及β 1A-IGF-IR复合物在前列腺癌进展中的作用。本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，并将在前列腺癌治疗中进行新的靶点验证。

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.