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.
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