Cell adhesion receptors, referred to as integrins, are recognized as key regulators of cellular processes including growth and differentiation. Integrins communicate with growth factor receptors (GFRs) to control specific cellular responses to stimuli originating in the extracellular environment. In this article, we review the role of integrins as molecular switches that modulate GFR activation and specificity. We also examine the reciprocal modulation of integrin functions by GFRs and the mechanisms through which those actions are fine-tuned.

Despite the findings that β1 integrins play a vital role in the regulation of cell proliferation and survival, the mechanisms through which they operate and lead to cancer progression remain elusive. Previously, our laboratory has shown that β1A integrins support insulin-like growth factor 1 (IGFI)-mediated mitogenic and transforming activities. Here we report that β1A integrins regulate basal levels of IGF-IR, although they are not critical for maintaining cancer cell morphology. Upon transfection of β1A siRNA and consequent downregulation of IGF-IR, we show inhibition of anchorage-independent growth of prostate cancer cells, a function which is dependent on IGF-IR expression. In addition, we demonstrate that IGFI-mediated activation of androgen receptor (AR), known to occur in prostate cancer cells, requires expression of β1A integrins as evaluated by luciferase reporter assays and immunoblotting analysis. Since β1A integrin levels are increased by R1881 or dihydrotestosterone (DHT), our results imply that β1A integrins support an androgen-enhanced feedback loop that regulates the expression of IGF-IR. β1A integrins also regulate inducible levels of IGF-IR in cells stimulated by androgen or by a combination of androgen and IGFI, as evaluated by flow cytometric analysis and immunoblotting. Furthermore, upon transfection of β1A siRNA and consequent downregulation of IGF-IR, neither activation of AKT, an effector of IGF-IR, nor AR levels are affected. We conclude that β1A integrin expression is critical for maintaining the regulatory crosstalk between IGF-IR and AR.