Protein tyrosine phosphatase 1B negatively regulates macrophage development through CSF-1 signaling

Abstract

Protein tyrosine phosphatase 1B (PTP-1B) is a ubiquitously expressed cytosolic phosphatase with the ability to dephosphorylate JAK2 and TYK2, and thereby down-regulate cytokine receptor signaling. Furthermore, PTP-1B levels are up-regulated in certain chronic myelogenous leukemia patients, which points to a potential role for PTP-1B in myeloid development. The results presented here show that the absence of PTP-1B affects murine myelopoiesis by modifying the ratio of monocytes to granulocytes in vivo. This bias toward monocytic development is at least in part due to a decreased threshold of response to CSF-1, because the PTP-1B ؊͞؊ bone marrow presents no abnormalities at the granulocytemonocyte progenitor level but produces significantly more monocytic colonies in the presence of CSF-1. This phenomenon is not due to an increase in receptor levels but rather to enhanced phosphorylation of the activation loop tyrosine. PTP-1B ؊͞؊ cells display increased inflammatory activity in vitro and in vivo through the constitutive up-regulation of activation markers as well as increased sensitivity to endotoxin. Collectively, our data indicate that PTP-1B is an important modulator of myeloid differentiation and macrophage activation in vivo and provide a demonstration of a physiological role for PTP-1B in immune regulation.hematopoiesis ͉ innate immunity ͉ myeloid progenitor cells P rotein tyrosine phosphatase 1B (PTP-1B; also known as PTPN1) is a ubiquitously expressed cytosolic phosphatase that is localized to the endoplasmic reticulum (1). PTP-1B Ϫ͞Ϫ mice were shown to be resistant to diet-induced diabetes and obesity (2-5), and the enzyme has been implicated in several metabolic pathways because of its ability to dephosphorylate and thereby down-regulate the activity of the insulin receptor (2, 3), epidermal growth factor receptor and platelet-derived growth factor receptor (6-8), insulin-like growth factor type I receptor (4, 9), and JAKs associated with cytokine family receptors, including leptin (5, 10) and growth hormone receptors (11). PTP-1B appears to show specificity toward JAK2 and TYK2 (12), and has been shown to regulate IFN signaling in fibroblasts (12). Despite the regulatory role in cytokine signaling, no immunological phenotype has been attributed to the PTP-1B-deficient mice to date.IL-3, granulocyte colony-stimulating factor (G-CSF), and granulocyte-monocyte colony-stimulating factor (GM-CSF) are cytokines that depend on JAK2 activity for signaling (13-15) and play important roles in the regulation of myeloid development (16). The receptor for another important myeloid cytokine, CSF-1, belongs to the class III receptor tyrosine kinase family together with the platelet-derived growth factor receptor (17), and it also activates TYK2 (18). Furthermore, it has been shown previously that PTP-1B protein levels are up-regulated in cell lines derived from chronic myelogenous leukemia patients (19)(20)(21). These observations led us to investigate the role of PTP-1B in hematopoiesis and, in particular, myelopoie...

Protein-Tyrosine Phosphatase 1B Is Required for HER2/Neu–Induced Breast Cancer

“…For example, recent studies have emphasized the complex roles of cells of the immune system in both promoting and protecting against cancer (18,19). PTP1B À/À mice exhibit altered macrophage function, an accumulation of B cells in bone marrow and lymph nodes and an increased percentage of B cells in blood, which could contribute to altered HER2-evoked tumor incidence (20,21). In the regard, PTP1B À/À mammary tumors seemed to contain much higher levels of immunoglobulin than those from WT mice.…”

NRAMP-1 Expression Modulates Protein-tyrosine Phosphatase Activity in Macrophages

“…In extension of previous observations (14, 50), we show that the higher nuclear translocation and DNA binding activity of NF-B and STAT1 in response to LPS and IFN-␥ in NRAMP-1-expressing cells correlates with higher phosphorylation of protein members of the mitogen-activated protein kinase and JAK/STAT signaling pathways. Several PTPs have been shown to regulate LPS and IFN-␥ signaling, including SHP-1 (32-34, 39, 61), PTP1B (62,63), TCPTP (64,65), mitogen-activated protein kinase phosphatases (66), and SHP-2 (67). In this line of thought, we sought to evaluate the status of PTP activity in response to NRAMP-1 expression.…”

Pancreatic Protein Tyrosine Phosphatase 1B Deficiency Exacerbates Acute Pancreatitis in Mice

“…46 In addition, PTP1B deficient macrophages display increased inflammatory activity in vitro and in vivo. 47 Moreover, PTP1B deficiency exacerbates inflammation and accelerates leukocyte trafficking in vivo. 48 Furthermore, PTP1B deficiency accentuates the effects of proinflammatory stimuli in both rodent and human macrophages.…”