PRLs (PRL1, 2, 3)

PTP4A1, 2, 3

The Phosphatase of Regenerating Liver (PRL) -1, 2, 3 (also known as PTP4A1, 2, 3) are members of the protein tyrosine phosphatase (PTP) family. The PRL sub-family comprises three members of approximately 20 kDa with at least 75% amino acid sequence identity having a prenylation motif at the C-terminus, which guides their localization to the endosomal compartment and the plasma membrane (Zeng et al., 2000) .

The PRL phosphatases gained much attention given their numerous associations with cell proliferation, cell invasion/migration, and metastasis (see reviews (Al-Aidaroos and Zeng, 2010) and (Rios et al., 2013)). They are highly expressed in the majority of human solid tumors, as well as hematological cancers, and are considered the most oncogenic of all PTPs. In spite of an increasing number of cancer-related studies, their mechanisms of oncogenic transformation, metastasis, and normal physiological function are not well understood.

Our specific interest in PTP-PRLs began when we found PRL-2 among a set of highly overexpressed genes in human breast cancer tissues and even more elevated in metastasized tumor in lymph node (Hardy et al., 2010) . We further demonstrated that co-expression of PRL-2 and ErbB2 in transgenic mice resulted in faster mammary tumor formation by an unknown mechanism (Hardy et al., 2010) . These findings suggest that PRL-2 is a major, if not essential contributor to breast cancer development and its metastasis. Although activity of the PTP-PRLs is reported in a broad array of signaling networks, their exact mechanism of action remain unclear until we uncovered that PTP-PRLs is an exquisite modulator of intracellular magnesium (Hardy et al., 2014) . In this study, we identified the CNNM magnesium transporters as key partners of PTP-PRLs, and interestingly this complex is evolutionarily highly conserved. These original findings have led us to propose a new paradigm in oncology, where a PTP controls the activity of a magnesium transporter to promote a rise in the intracellular magnesium cations, causing an increase in tumor growth and metastasis (Hardy et al., 2014) .

The CNNM proteins, that comprise 4 paralogues (CNNM1-4) in mammals, have homologues within all cells from prokaryotes and fungi, to plants. Since magnesium cations are essential partners for ATP and many metabolic enzymes, regulating intracellular magnesium levels is critical in the response of all living organisms to their environment. We believe that PRLs evolved to regulate this fundamental process to sustain their bioenergetics needs.

Therefore, part of our research program is centered on the discovery of this remarkable linkage between a subfamily of PTPs and a group of four evolutionarily conserved magnesium transporters. Using innovative techniques, we examine the function of this novel biochemical regulation, understand its physiological significance and validate the potential of PTP-PRLs as therapeutic targets in various diseases including cancer.