Researchers have known for decades that signaling events in the cytoplasm can have profound effects on signaling events in the nucleus;however details regarding how this cytoplasm to nuclear ("outside-inside") cross talk is regulated are stil not known. We have recently discovered that paxillin, a molecule best known for regulating cytoskeletal remodeling, is a critical liaison between extranuclear and intranuclear signaling in prostate cancer cells. Specifically, we find that paxillin is necessary for extranuclear Erk activation in response to multiple inputs, including nongenomic androgen signaling via membrane-localized androgen receptors (ARs) as well as growth factors via Receptor Tyrosine Kinases (RTKs). Once activated, Erk then regulates phosphorylation of paxillin on serine residues, at which point phosphoserine-paxillin travels to the nucleus and mediates AR- and Erk-dependent transcription. In fact, if we prevent this Erk-mediated phosphorylation of paxillin, then paxillin will not enter the nucleus, androgen and growth factor-dependent transcription is abrogated, and prostate cancer cells do not proliferate in response to any of these agonists. Importantly, we find that cytoplasmic paxillin and nuclear phosphoserine-paxillin expression are upregulated in human prostate cancer relative to normal prostate tissue, implying that paxillin is over-active in tumors. Together, our data suggest that paxillin might be a key mediator of prostate cancer growth and therefore a viable diagnostic and therapeutic target. Furthermore, since paxillin actually regulates Erk activation and downstream effects in every tumor cell line tested, regardless of origin, we postulate that paxillin might be a general regulator of Erk action well beyond the prostate. In this proposal, we will continue to focus on prostate cancer models to further elucidate how paxillin regulates "outside-inside" signaling in response to growth factors, androgens, and other steroids. In addition, we will examine paxillin effects on prostate cancer growth in-vivo, and will more closely examine paxillin expression and activation in human prostate cancer. Finally, we will test novel means of specifically regulating paxillin's actions in the nucleus while sparing it's actions in the cytoplasm, thereby using nuclear paxillin as a target for the treatment of both castration-sensitive and castration-resistant prostate cancer growth.
Prostate cancer growth is regulated by androgens and growth factors. All of these factors stimulate kinase signaling that originates at the plasma membrane. These kinase signals then transmit information to the nucleus, where changes in gene expression drive cancer cells to proliferate. We propose to study how these signals outside the nucleus are able to mediate events inside the nucleus, focusing on a novel protein called paxillin.
|Sen, Aritro; Prizant, Hen; Light, Allison et al. (2014) Androgens regulate ovarian follicular development by increasing follicle stimulating hormone receptor and microRNA-125b expression. Proc Natl Acad Sci U S A 111:3008-13|