TGF-β cascade regulation by PPP1 and its interactors – impact on prostate cancer development and therapy

TGF-β signaling pathway plays a pivotal role in a wide variety of diseases, including prostate cancer. Interestingly, TGF-β exhibits a dual role in cancer, since in late-stage tumours, the cellular machinery subverts the signalling pathway to promote the cancer progression. A common mechanism used by cells to either propagate or terminate intracellular signal transduction pathways is the reversible protein phosphorylation. In cancer, imbalances in protein phosphorylation system, involving either protein kinases or protein phosphatases, appear to be an important pathophysiological mechanism. An increasing number of protein phosphatases, particularly of the serine/threonine phosphatases family, have been reported to regulate the TGF-β pathway through interactions with its mediators. Hence, protein phosphatases have been explored as new targets to cancer therapy. In this review we described the relevance of TGF-β pathway in prostate carcinogenesis and discussed the role of PPP1, one of the major serine/threonine phosphatases, in the regulation of several TGF-β signalling members.

Authors and Affiliations:

Luís Korrodi Gregório, Joana Vieira Silva, Luís Sousa, Maria João Freitas, Juliana Felgueiras, Margarida Fardilha

Laboratório de Transdução de Sinais, Centro de Biologia Celular, Departamento de Biologia, Secção Autónoma de Ciências da Saúde, Universidade de Aveiro, Aveiro, Portugal

Abstract:

Protein phosphorylation is a key mechanism by which normal and cancer cells regulate their main transduction pathways. Protein kinases and phosphatases are precisely orchestrated to achieve the (de)phosphorylation of candidate proteins. Indeed, cellular health is dependent on the fine-tune of phosphorylation systems, which when deregulated lead to cancer. Transforming growth factor beta (TGF-b) pathway involvement in the genesis of prostate cancer has long been established. Many of its members were shown to be hypo- or hyperphosphorylated during the process of malignancy. A major phosphatase that is responsible for the vast majority of the serine/threonine dephosphorylation is the phosphoprotein phosphatase 1 (PPP1). PPP1 has been associated with the dephosphorylation of several proteins involved in the TGF-b cascade. This review will discuss the role of PPP1 in the regulation of several TGF-b signalling members and how the subversion of this pathway is related to prostate cancer development. Furthermore, current challenges on the protein phosphatases field as new targets to cancer therapy will be addressed.

Journal:

Journal of Cellular and Molecular Medicine

Link:

http://onlinelibrary.wiley.com/journal/10.1111/(ISSN)1582-4934