Expression of PRL-1 nuclear PTPase is associated with proliferation in liver but with differentiation in intestine

Abstract

Mechanisms controlling the tyrosine phosphorylation of cellular proteins are important in the regulation of cellular processes including growth and differentiation. It has become clear that a number of protein tyrosine phosphatases (PTPases) that dephosphorylate tyrosyl residues may play a role in the growth response, both in growth-promoting and growth-inhibiting capacities. We identified PRL-1, a unique nuclear PTPase that is an immediate-early gene in liver regeneration and is positively associated with growth, including fetal and neoplastic hepatic growth and anchorage-independent growth after overexpression in fibroblasts. In this study, we show that PRL-1 nuclear protein levels in regenerating liver parallel those of its mRNA, although the peak occurs later, just before the onset of DNA synthesis. We further show that PRL-1 is significantly expressed in intestinal epithelia and that, in contrast to the expression pattern of PRL-1 in liver, its expression is associated with cellular differentiation in intestine. Specifically, PRL-1 is expressed in villus but not crypt enterocytes and in confluent differentiated but not undifferentiated proliferating Caco-2 colon carcinoma cells. The expression of PRL-1 in intestine shows inverse correlation with proliferating cell nuclear antigen expression, a marker for S-phase cells. These results suggest that PRL-1 may play different roles in these two digestive tissues. Such a dichotomy of roles has previously been described for some protein tyrosine kinases and might be due to the availability of alternate substrates in different tissues.

Mitogenic Up-regulation of the PRL-1 Protein-tyrosine Phosphatase Gene by Egr-1

“…Egr-1 activated the PRL-1 promoter primarily via the Ϫ99 site. The Egr-1 binding motif was necessary for transcriptional induction of the PRL-1 gene following mitogen stimulation of NIH 3T3 cells (5). This result supports the involvement of Egr-1 in PRL-1 gene transcription during liver regeneration as well when Egr-1 is even more rapidly induced than in mitogentreated 3T3 cells.…”

“…For example, in intestinal epithelia that contain both terminally differentiated and proliferating cells, PRL-1 is expressed in the terminally differentiated villus but not proliferating crypt enterocytes (5). As consensus CdxA sites are present in PRL-1 promoter P1, Cdx homeodomain proteins, which control intestinal differentiation, may contribute to this differentiation related expression of the PRL-1 gene (6,39).…”

“…The phosphatase of regenerating liver-1 (PRL-1) 1 gene encodes an evolutionarily conserved nuclear protein-tyrosine phosphatase, and its expression is highly induced in liver regeneration and mitogen-stimulated fibroblasts (1)(2)(3)(4)(5). Overexpression of PRL-1 in transfected NIH 3T3 cells modifies cell growth (3).…”

“…PRL-1 may play an important role in cell growth via regulation of protein tyrosine phosphorylation and dephosphorylation of specific substrates that remain unknown (4). Expression of the PRL-1 gene is positively associated not only with cellular growth during liver regeneration, development, and oncogenesis but also with differentiation in intestine and other tissues (5).…”

PRL phosphatases as potential molecular targets in cancer

“…PRL expression in normal tissues seems to correlate most often with terminal differentiation. For example, PRL-1 and PRL-3 expression in the intestine is limited to the terminally differentiated villus but not found in proliferating crypt enterocytes (8,20). In addition, expression of PRL-3 in heart tissue is primarily found in cardiomyocytes (18).…”