PTPN13 regulates cellular signalling and β-catenin function during megakaryocytic differentiation

Abstract

PTPN13 is a high-molecular weight intracellular phosphatase with several isoforms that exhibits a highly modular structure. Although in recent years different roles have been described for PTPN13, we are still far from understanding its function in cell biology. Here we show that PTPN13 expression is activated during megakaryocytic differentiation at the protein and mRNA level. Our results show that the upregulation of PTPN13 inhibits megakaryocytic differentiation, while PTPN13 silencing triggers differentiation. The ability of PTPN13 to alter megakaryocytic differentiation can be explained by its capacity to regulate ERK and STAT signalling. Interestingly, the silencing of β-catenin produced the same effect as PTPN13 downregulation. We demonstrate that both proteins coimmunoprecipitate and colocalise. Moreover, we provide evidence showing that PTPN13 can regulate β-catenin phosphorylation, stability and transcriptional activity. Therefore, the ability of PTPN13 to control megakaryocytic differentiation must be intimately linked to the regulation of β-catenin function. Moreover, our results show for the first time that PTPN13 is stabilised upon Wnt signalling, which makes PTPN13 an important player in canonical Wnt signalling. Our results show that PTPN13 behaves as an important regulator of megakaryocytic differentiation in cell lines and also in murine haematopoietic progenitors. This importance can be explained by the ability of PTPN13 to regulate cellular signalling, and especially through the regulation of β-catenin stability and function. Our results hold true for different megakaryocytic cell lines and also for haematopoietic progenitors, suggesting that these two proteins may play a relevant role during in vivo megakaryopoiesis.

Lysine methyltransferase SMYD2 promotes cyst growth in autosomal dominant polycystic kidney disease

“…We identified that PTPN13 as a transcriptional target of SMYD2. PTPN13 is one of the members of the PTP family, which regulates a variety of cellular processes and oncogenic transformation by removing phosphate groups from phosphorylated residues on proteins, including ERK and STAT (31). SMYD2 is able to downregulate the expression of PTPN13 in cystic renal epithelial cells (Supplemental Figure 9).…”

“…PTPN13 regulates a variety of cellular processes and oncogenic transformation by removing phosphate groups from phosphorylated tyrosine residues on proteins, including ERK and STAT (31). Since knockdown of Smyd2 and inhibition of SMYD2 with AZ505 decreased the phosphorylation of ERK, S6, and Akt in cystic renal epithelial cells (Figure 7, A and B), and knockout of Smyd2 led to jci.org Volume 127…”

NSD2 overexpression drives clustered chromatin and transcriptional changes in a subset of insulated domains

“…These include the protein tyrosine phosphatase gene, PTPN13 60,61 , FGF13 62 and ETV5 63,64 . The PTPN13 gene, which regulates cell growth 65 , differentiation 60 , mitotic cycle, and oncogenic transformation is located within a CTCF-mediated loop which harbors significant changes in CTCF and H3K27ac (Fig. 6a left), and it is found within a region that undergoes B to A compartment switching.…”

Microenvironmental regulation of hematopoietic stem cells and its implications in leukemogenesis

“…Wnt regulation of HSCs appears to be mediated in part through its effects on HSC adhesion in the niche. Two downstream effectors of Wnt, β-catenin and the phosphatase PTPN13, are important in this process [37, 38*]. Knockdown of these effectors in murine Lin − cells increased the fraction of LT-HSCs, increased HSC and progenitor adhesion in the BM, decreased cell cycling and proliferation, and was associated with upregulation of several CAM genes ( ITGA4, CDH1, CDH12, NCAM2, and RELN ) [38*].…”