Protein Tyrosine Phosphatase 1B in Hematopoiesis

Abstract

Previously published online as a Cell Cycle E-publication: http://www.landesbioscience.com/journals/cc/abstract.php?id=2735 KEY WORDSprotein tyrosine phosphatase 1B, myeloid development, monocyte/macrophage, colonystimulating factor-1 ABBREVIATIONS PTPprotein tyrosine phosphatase RTK receptor tyrosine kinase CML chronic myelogenous leukemia CSF colony stimulating factor G CSF granulocyte CSF GM CSF granulocyte monocyte CSF Perspective Protein Tyrosine Phosphatase 1B in Hematopoiesis ABSTRACTProtein tyrosine phosphatase 1B (PTP-1B) is a ubiquitously expressed cytosolic phosphatase best known for its role in insulin signaling. Despite the fact that it is highly expressed in hematopoietic tissues and has been shown to downregulate cytokine receptor signaling, no physiological role for PTP-1B in immune regulation had been reported. Our recent results show that the absence of PTP-1B affects murine myelopoiesis through increased phosphorylation of the CSF-1 receptor tyrosine kinase. Here we further discuss the role of PTP-1B in monocyte/macrophage differentiation as well as the implications of our findings in the context of PTP-1B inhibitors.Protein tyrosine phosphatase 1B (PTP-1B; also known as PTPN1) is a ubiquitously expressed cytosolic phosphatase that is anchored to the endoplasmic reticulum (ER) membrane. 1 It was the first PTP to be identified 2 and to have its crystal structure resolved, 3 and it has since become the prototypic nontransmembrane PTP. PTP-1B regulates several receptor tyrosine kinases (RTKs), including EGFR, 4,5 PDGFR, 5-7 insulin receptor 8-10 and IGF-IR. 11,12 In addition to RTKs, PTP-1B has other membrane-associated substrates: it has been shown to regulate integrin signaling through Src, 13 focal adhesion kinase (FAK) and α-actinin 14 as well as the adaptor protein p130cas. 15 PTP-1B can also dephosphorylate the negative regulator p62dok 7 and thus positively influence Ras signaling. The oncoprotein p210 Bcr-Abl, which is found in chronic myelogenous leukemia (CML), is another substrate of PTP-1B, and certain CML-derived cell lines overexpress PTP-1B. 16 Lastly, PTP-1B can regulate cytokine signaling through dephosphorylation of Jak2 and Tyk2 downstream of leptin, 17,18 growth hormone, 19 IFN-γ and IFN-α/β, 20 through dephosphorylation of Stat5a/b downstream of prolactin 21 as well as through a direct association with the Epo receptor. 22 The physiological relevance of some of these interactions and substrates still remains to be explored. PTP-1B AND METABOLIC SYNDROMEThe PTP-1B deficient mice were created by our laboratory and that of B. Neel (Harvard University) with essentially identical phenotypes. 9,10 When fed ad libitum, ptp1b -/-mice had lower blood glucose and lower blood insulin than the ptp1b +/+ littermates 9 and they presented a decrease in fat mass due to adipocyte hypotrophy. 10 They also displayed higher glucose tolerance and lower glucose levels after exogenous insulin. 9 On high-fat diet, ptp1b -/-mice gained less weight due to increased basal metabolic rate and increased g...

Protein Tyrosine Phosphatases: Emerging Regulators of Apoptosis

“…10 Inactivation of the PTP-1B gene, a close homologue of TC-PTP, perturbs myeloid differentiation causing an abnormal monocyte/granulocyte ratio. 66,67 The enhanced sensitivity of monocytes to CSF-1 provides a potential mechanism for their resistance to apoptosis. 66 The PTP-PEP, exclusively expressed in hematopoietic cells, 68 is involved in B cell receptor induced growth arrest and programmed cell death.…”

Multi-omics analyses of tumor-associated immune-infiltrating cells with the novel immune checkpoint protein tyrosine phosphatase 1B (PTP1B) in extracellular matrix of brain-lower-grade-glioma (LGG) and uveal-melanoma (UVM)

“…PTP1B is an important molecule in the body’s immune regulation ( 4 ). First, we explored expression of PTP1B in different types of normal tissues and found that PTP1B was most highly expressed in respiratory system and bone marrow & lymphoid, followed by kidney & urinary bladder, gastrointestinal tract, proximal digestive tract and female tissues ( Figure S1A ).…”

“…PTP1B (encoded by PTPN1) belongs to the protein tyrosine phosphatase family ( 4 ). Together with protein tyrosine kinases, they maintain the balance of tyrosine protein phosphorylation, participates in cell signal transduction, and regulates cell growth, differentiation, metabolism, gene transcription and immunity ( 5 ).…”

Critical roles of PTPN family members regulated by non-coding RNAs in tumorigenesis and immunotherapy

“…PTPN1 negatively regulates macrophage development through macrophage-colony stimulating factor 1 (CSF-1) signaling. Mechanistically, PTPN1 deficiency tends to make cells more sensitive to CSF-1, resulting in increased phosphorylation of the CSF-1 receptor (CSF-1R) in bone marrow-derived macrophages and increased inflammatory activity, implying that PTPN1 is a critical regulator of bone marrow differentiation and macrophage activation in vivo ( 174 , 175 ).…”