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Interaction of the Protein Kinase C‐related Kinases with the TPα and TPβ isoforms of the T Prostanoid Receptor: Role in Thromboxane‐induced Neoplastic Responses
Author(s) -
Mulvaney Eamon,
O'Sullivan Aine,
Hyland Paula,
Kinsella B
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.934.4
Subject(s) - cancer research , kinase , agonist , thromboxane receptor , androgen receptor , rhoa , biology , prostate cancer , receptor , chemistry , microbiology and biotechnology , signal transduction , endocrinology , cancer , medicine , biochemistry
In humans, thromboxane (TX) A 2 signals through the TPα and TPβ isoforms of the T prostanoid receptor (TP). There is increasing evidence of a role for TXA 2 and TPα/TPβ in neoplasms including in prostate, colon and bladder cancer. Mechanistically, we previously identified protein kinase C‐related kinase (PRK) 1 as an interactant of TPα/TPβ, a functional interaction essential for TPα/TPβ‐induced prostate cancer (PCa) cell migration. Moreover, agonist‐activation of TPα/TPβ induced phosphorylation of histone H3 at Thr11 (H3Thr11), a recognized epigenetic marker of androgen‐induced chromatin remodelling. As PRK1/PKN1 is a member of a wider subfamily including PRK2/PKNγ and PRK3/PKNβ which, like PRK1, are also widely implicated in cancer progression, herein the interaction of TPα/TPβ with PRK2 and PRK3 was investigated. Both PRK2 and PRK3 were confirmed to interact with TPα and TPβ, interactions dynamically regulated in response to TP‐agonist activation. Agonist‐activation of the TPs also led to activation of all three PRKs. Furthermore, PRK1 and PRK2, but not PRK3, were found to interact with TPα and TPβ in PC‐3 cells, and targeted disruption of PRK1 and PRK2, but not PRK3, impaired TP‐mediated H3Thr11 phosphorylation, cell proliferation, migration and invasion in the PCa cell line. Considering the critical roles of TPα/TPβ and of the PRKs in cancer progression, the discovery of these distinct, yet regulated, interactions is likely to be functionally significant, not least in cancer, but also in other pathophysiological settings where aberrant PRK and/or TP expression or function are implicated. Funded by the Irish Cancer Society, Health Research Board Ireland and the Movember Foundation (PCI12KIN, MRCG/2012/3).