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Interaction of Protein Kinase C‐related Kinase (PRK) 1 with the TPα and TPβ isoforms of the human Thromboxane A2 receptor: Implications for Prostate Cancer

In humans, thromboxane (TX)A2 signals through the TPα and TPβ isoforms of the TXA2 receptor (TP). Here, the RhoA effector protein kinase C‐related kinase (PRK) 1 was identified as an interactant of both TPα and TPβ involving common and unique sequences within their respective carboxyl‐termini and the kinase domain of PRK1. While the interaction with PRK1 is constitutive, agonist‐activation of TPα/TPβ did not regulate the complex but enhanced PRK1 activation leading to phosphorylation of histone H1 in vitro. Altered PRK1/TP expression & signaling are increasingly implicated in certain neoplasms, particularly in androgen‐associated prostate carcinomas. Agonist‐activation of TPα/TPβ led to phosphorylation of histone H3 at Thr11 (H3Thr11), a recognized marker of androgen induced‐chromatin remodeling, in the prostate LNCaP and PC‐3 cell lines but not in primary vascular smooth muscle or endothelial cells. Moreover, this effect was augmented by dihydrotestosterone in androgen‐responsive LNCaP but not in non‐responsive PC‐3 cells. Disruption of PRK1 impaired TPα/TPβ‐mediated H3Thr11 phosphorylation in, and cell migration of, both cell types. Given the role of TXA2 as a potent mediator of RhoA signaling, the identification of PRK1 as a bone fide interactant of TPα/TPβ has broad functional significance such as within the vasculature and in neoplasms in which both PRK1 and the TPs are increasingly implicated. Funded by SFI and HRB.