The phosphatase PRL-3 affects intestinal homeostasis by altering the crypt cell composition

Abstract

Expression of the phosphatase of regenerating liver-3 (PRL-3) is known to promote tumor growth in gastrointestinal adenocarcinomas, and the incidence of tumor formation upon inflammatory events correlates with PRL-3 levels in mouse models. These carcinomas and their onset are associated with the impairment of intestinal cell homeostasis, which is regulated by a balanced number of Paneth cells and Lgr5 expressing intestinal stem cells (Lgr5+ ISCs). Nevertheless, the consequences of PRL-3 overexpression on cellular homeostasis and ISC fitness in vivo are unexplored. Here, we employ a doxycycline-inducible PRL-3 mouse strain to show that aberrant PRL-3 expression within a non-cancerous background leads to the death of Lgr5+ ISCs and to Paneth cell expansion. A higher dose of PRL-3, resulting from homozygous expression, led to mice dying early. A primary 3D intestinal culture model obtained from these mice confirmed the loss of Lgr5+ ISCs upon PRL-3 expression. The impaired intestinal organoid formation was rescued by a PRL inhibitor, providing a functional link to the observed phenotypes. These results demonstrate that elevated PRL-3 phosphatase activity in healthy intestinal epithelium impairs intestinal cell homeostasis, which correlates this cellular mechanism of tumor onset with PRL-3-mediated higher susceptibility to tumor formation upon inflammatory or mutational events.Key messages• Transgenic mice homozygous for PRL-3 overexpression die early.• PRL-3 heterozygous mice display disrupted intestinal self-renewal capacity.• PRL-3 overexpression alone does not induce tumorigenesis in the mouse intestine.• PRL-3 activity leads to the death of Lgr5+ ISCs and Paneth cell expansion.• Impairment of cell homeostasis correlates PRL-3 action with tumor onset mechanisms.

Targeting protein phosphatases for the treatment of inflammation-related diseases: From signaling to therapy

“…Increasing PRL3 phosphatase activity has been shown to lead to higher susceptibility to colitis-associated colorectal cancer following inflammatory or mutational events. 208 In MKPs, DUSP1/6 inactivates MAPKs by dephosphorylation of Thr or Tyr residues within the activation loop, thereby regulating many cellular signals in immune responses. DUSP1/6 were reported to serve as crucial regulators in PM2.5 exposure and COVID-19 infection or to induce proinflammatory immune responses in lung epithelial or endothelial cells through regulation of MAPK signals and NF-κB signaling.…”

Knockdown of phosphatases of regenerating liver‐1 prolongs the lifespan of Caenorhabditis elegans via activating DAF‐16/FOXO

“…In fact, the association of prl-1 with the intestine was not unexpected, as elevated activity of PRL-3 impaired cellular homeostasis of intestinal epithelial cells in healthy human. 53 Hence, these results suggested that knockdown of prl-1 not only extended C. elegans lifespan, but also enhanced essential physiological functions associated with later life activity, demonstrating that PRL-1 plays a crucial role in regulating the C. elegans life cycle. However, it is still unclear whether PRLs play an equally important role in mammalian lifespan as they do in C. elegans lifespan.…”

“…Taking these factors together, we speculated that prl‐1 might be related to the development and function of C. elegans intestine. In fact, the association of prl‐1 with the intestine was not unexpected, as elevated activity of PRL‐3 impaired cellular homeostasis of intestinal epithelial cells in healthy human 53 . Hence, these results suggested that knockdown of prl‐1 not only extended C. elegans lifespan, but also enhanced essential physiological functions associated with later life activity, demonstrating that PRL‐1 plays a crucial role in regulating the C. elegans life cycle.…”

Protein Tyrosine Phosphatase PRL-3: A Key Player in Cancer Signaling

“…PRL-3 upregulation in colon cancer cells and primary fibroblasts induces telomere structural abnormalities, telomere deprotection, DNA damage response, chromosomal instability, and senescence, contributing to tumor progression [ 121 ]. Additionally, heightened PRL-3 phosphatase activity in the healthy intestinal epithelium disrupts intestinal cell equilibrium, increasing vulnerability to PRL-3-mediated inflammation or mutation, which may lead to tumor development [ 122 ]. Moreover, PRL-3 has been shown to interact with cyclin and CBS domain divalent metal cation transport mediator (CNNM) to regulate the intracellular concentration of calcium and magnesium plasma [ 123 , 124 ].…”