Protein Tyrosine Phosphatase PRL2 Mediates Notch and Kit Signals in Early T Cell Progenitors

Abstract

The molecular pathways regulating lymphoid priming, fate, and development of multipotent bone marrow hematopoietic stem and progenitor cells (HSPCs) that continuously feed thymic progenitors remain largely unknown. While Notch signal is indispensable for T cell specification and differentiation, the downstream effectors are not well understood. PRL2, a protein tyrosine phosphatase that regulates hematopoietic stem cell proliferation and self-renewal, is highly expressed in murine thymocyte progenitors. Here we demonstrate that protein tyrosine phosphatase PRL2 and receptor tyrosine kinase c-Kit are critical downstream targets and effectors of the canonical Notch/RBPJ pathway in early T cell progenitors. While PRL2 deficiency resulted in moderate defects of thymopoiesis in the steady state, de novo generation of T cells from Prl2 null hematopoietic stem cells (HSCs) was significantly reduced following transplantation. Prl2 null HSPCs also showed impaired T cell differentiation in vitro. We found that Notch/RBPJ signaling upregulated PRL2 as well as c-Kit expression in T cell progenitors. Further, PRL2 sustains Notch-mediated c-Kit expression and enhances SCF/c-Kit signaling in T cell progenitors, promoting effective DN1-DN2 transition. Thus, we have identified a critical role for PRL2 phosphatase in mediating Notch and c-Kit signals in early T cell progenitors.

Physiological and oncogenic roles of the PRL phosphatases

“…PRL-2 KO thymocyte characterization recapitulated the previously observed HSC G0 arrest phenotype, but in DN2a and DN2b T cell progenitor subsets instead [63]. Furthermore, in a T-cell transfer model, there was an accumulation of early T cell progenitors, DN2, and DN3 cells in the thymus of hosts receiving PRL-2 KO HSCs [63].…”

“…Interestingly, expression of the PTEN protein was elevated and stem cell factor (SCF)‐Kit‐induced Akt activation was attenuated in PRL‐2 KO germ cells . Similarly, Kit or Akt activation was diminished in PRL‐2 KO HPSC following SCF stimulation . These results suggest that PRL‐2 promotes cell survival through SCF/Kit‐mediated PI3K/Akt activation by possibly downregulating PTEN during spermatogenesis, HSPC proliferation, and T‐cell development.…”

“…This was attributed to the lack of PRL-2, leading to increased PTEN expression, Akt and ERK pathway inhibition, and ultimately resulting in altered expression of the cell cycle regulators p21, p57, Cyclin D1, and Cyclin E1 [62]. Another publication by the same group identified a PRL-2-regulated positive feedback loop between c-Kit and Notch1, which impacts early T-cell development [63]. PRL-2 KO thymocyte characterization recapitulated the previously observed HSC G0 arrest phenotype, but in DN2a and DN2b T cell progenitor subsets instead [63].…”

“…Another publication by the same group identified a PRL-2-regulated positive feedback loop between c-Kit and Notch1, which impacts early T-cell development [63]. PRL-2 KO thymocyte characterization recapitulated the previously observed HSC G0 arrest phenotype, but in DN2a and DN2b T cell progenitor subsets instead [63]. Furthermore, in a T-cell transfer model, there was an accumulation of early T cell progenitors, DN2, and DN3 cells in the thymus of hosts receiving PRL-2 KO HSCs [63].…”

Phosphatase PRL2 promotes AML1-ETO-induced acute myeloid leukemia

“…8 Recently, we found that PRL2 mediates NOTCH and KIT signals in early T cell progenitors and that PRL2 is essential for oncogenic NOTCH1-induced T cell leukemia in vivo . 9–10 An improved understanding of how PRLs function and how they are regulated may establish PRLs as novel therapeutic targets in acute myeloid leukemia.…”