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Role of the Adaptor Protein LNK in Normal and Malignant Hematopoiesis

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Role of the Adaptor Protein LNK in Normal and Malignant Hematopoiesis Oncogene (2013) 32, 3111–3118 & 2013 Macmillan Publishers Limited All rights reserved 0950-9232/13 www.nature.com/onc REVIEW Role of the adaptor protein LNK in normal and malignant hematopoiesis S Gery1 and HP Koeffler1,2 The signal transduction pathways, orchestrating the differentiation of hematopoietic stem and progenitor cells in response to cytokine stimulation, are strictly controlled by networks of feedback loops, highly selective protein interactions and finely tuned on/off switches. In hematological malignancies, the aberrant activation of signaling pathways is usually associated with mutations in tyrosine kinases. Recently, the role of negative signaling regulators is increasingly being recognized as an alternative mechanism involved in diseases such as leukemias and myeloproliferative neoplasms (MPNs). The adaptor protein LNK (Src homology 2 (SH2)B3) is a negative regulator of cytokine signaling that has an essential, nonredundant role in normal hematopoiesis. Indeed, LNK-deficient mice show marked expansion of early hematopoietic precursors, more mature myeloid and B-lineage lymphoid cells, as well as enhanced hematopoietic reconstitution. Murine models show that loss of LNK enhances the development of MPNs and may have a role in additional pathologies. LNK mutations were recently identified in patients with MPNs, and studies in animal models and hematopoietic cell lines suggest that LNK controls the aberrant signaling pathways induced by activated oncogenic kinases. In addition, genome-wide studies show that LNK is associated with autoimmune and cardiovascular disorders. These findings have implications for the future study of hematopoiesis, as well as for the development of novel stem cell and disease-specific therapies. Oncogene (2013) 32, 3111–3118; doi:10.1038/onc.2012.435; published online 8 October 2012 Keywords: cytokine signaling; LNK; hematopoiesis INTRODUCTION structure (Figure 1) with a N-terminal dimerization domain Throughout life, hematopoiesis is a continuing process, in which containing a phenylalanine zipper motif, which mediates homo- 14 hematopoietic stem cells (HSCs) replenish multilineage progeni- and heterodimerization of SH2B family members; proline-rich tors that further differentiate into all lineages of mature blood regions; a pleckstrin homology (PH) domain believed to recognize cells. Cytokines and their cognate receptors are key factors phosphoinositides and control cell membrane localization; influencing the function and survival of hematopoietic cells. The a SH2 domain essential for binding phosphotyrosine in target magnitude and kinetics of cytokine receptor activation is tightly proteins; and a conserved C-terminal CBL recognition motif. SH2B regulated at multiple levels to ensure a proper cellular response adaptor proteins are implicated in signal transduction pathways and prevent leukemic transformation. Dysregulation of signaling downstream of various RTKs, including receptors for insulin, by receptor tyrosine kinases (RTKs), as well as non-RTKs (i.e., Janus insulin-like growth factor I, nerve growth factor, platelet-derived kinases (JAKs)) is, a frequent event in cancer, particularly in growth factor (PDGF), fibroblast growth factor, stem cell hematopoietic malignancies.1,2 Adaptor proteins that bind RTKs factor (SCF)/c-KIT and macrophage colony-stimulating factor 15,16 and JAKs have an important role in the control of cytokine (M-CSF)/FMS, as well as JAKs. signaling pathways. These adaptor proteins usually lack enzymatic Deletion of SH2B1 in mice results in severe obesity, leptin 17 activity and instead serve as molecular platforms coordinating and insulin resistance, type 2 diabetes and infertility. Genetic signaling events. The Src homology 2 (SH2)B family is a group of studies have also indicated that SH2B1 has a key role in controlling adaptor proteins implicated in a broad range of signaling body weight and glucose homeostasis in humans. Deletion of APS pathways. Among mice deficient for SH2B family members, does not alter adiposity, energy balance or glucose metabolism, those who are LNK-deficient have the most prominent but may negatively regulate leptin and insulin sensitivity under 18 aberrations in hematopoiesis.3,4 Moreover, LNK mutations have certain conditions. LNK was originally cloned from a lymph node 19 recently been identified in myeloproliferative neoplasms (MPNs) cDNA library and shown to participate in T-cell signaling. Shortly and some leukemias,5–13 demonstrating the importance of LNK after, two groups generated LNK-deficient mice providing 3,4 not only for normal but also for aberrant hematopoiesis, thus important insights into LNK function in hematopoiesis. forming the rationale for this review. Although high levels of LNK are found in non-hematopoietic tissues such as the testis, brain and muscle, the only noticeable phenotypes of Lnk À / À mice are in the hematopoietic SH2B FAMILY compartments. Further studies established LNK as a key hub The SH2B family of adaptor proteins consists of SH2B1, APS integrating multiple signaling pathways in the hematopoietic/ (SH2B2) and LNK (SH2B3). These proteins share a common domain immunologic system. 1Hematology/Oncology, Cedars-Sinai Medical Center, UCLA School of Medicine, Los Angeles, CA, USA and 2Cancer Science Institute, National Cancer Institute, National University of Singapore, Singapore. Correspondence: Dr S Gery, Hematology/Oncology, Cedars-Sinai Medical Center, 8700 Beverly boulevard, Los Angeles, CA 90048, USA. E-mail: [email protected] Received 13 June 2012; revised 3 August 2012; accepted 4 August 2012; published online 8 October 2012 Adaptor protein LNK S Gery and HP Koeffler 3112 SH2B1 (PSM) Y HSC DD PH SH2 Tpo/JAK2 1756Myeloid Lymphoid progenitor progenitor APS (SH2B2) Y LNK DDPH SH2 1632MEP GMP ProB ProT IL-3, G-CSF, Lnk (SH2B3) Y FLT3, PDGF DDPH SH2 erythrocytes platelets granulocytes macrophages B cells T cells 1575 14-3-3 14-3-3 FLNA KIT CBL* (S13) (S129) FMS (Y572) PDGFRA Epo Tpo/JAK2 SCF, IL-7 PDGFRB M-CSF FLT3 JAK2 Figure 2. JAK3 LNK is a broad inhibitor of cytokine signaling pathways in LCK hematopoietic lineages. The major lineage-specific cytokine signal- TRKA ing pathways targeted by LNK and additional cytokine signaling MPL TCRζ pathways under LNK control are shown in red. Epo, erythropoietin; GMP, granulocyte macrophage progenitor; HSC, hematopoietic stem Figure 1. Schematic representation of SH2B family members. LNK- cells; M-CSF, macrophage colony-stimulating factor; MEP, mega- binding partners are shown below the LNK protein relative to their karyocyte erythroid progenitor; Tpo, thrombopoietin. main binding region. Interacting proteins for which the LNK-binding domain is unknown are not shown. *CBL-binding site is based on sequence homology.71 A full colour version of this figure is available at the Oncogene journal online. LNK IN NORMAL HEMATOPOIESIS BM. In addition, production of reactive oxygen species is increased À / À LNK in hematopoietic lineages in Lnk macrophages, and LNK inhibits M-CSF-induced LNK is highly expressed in multipotent hematopoietic cells and migration of macrophages. their precursors. Furthermore, expression levels of LNK are regulated during normal hematopoiesis, and enhanced by cytokine stimulation. Although LNK functions as a negative LNK in non-hematopoietic BM cells regulator of cytokine signaling in various lineages, the specific Non-hematopoietic (stromal) BM cells consist of a heterogeneous pathways targeted by LNK appear to differ between the lineages cell population, including fibroblasts, endothelial cells, osteoblasts (Figure 2). The most striking features of Lnk À / À mice are profound and osteoclasts, providing the structural microenvironment that splenomegaly with extramedullary hematopoiesis.3,4 The enlarged facilitates hematopoiesis. In addition to its strong expression in spleens of these mice had marked expansion of B lineage hematopoietic cells, LNK is also expressed in non-hematopoietic lymphocytes resulting in part from hypersensitivity of B cells BM cells. The aorta-gonad-mesonephros region is the first intra- precursors to SCF. LNK was originally reported to be involved in embryonic site for definitive hematopoiesis and LNK was found to T-cell receptor signal transduction; yet, T-cell development is be a negative regulator of hematopoiesis in this region.31 LNK was unaffected in LNK-deficient mice. detected in aorta-gonad-mesonephros endothelial cells and its Several studies demonstrated a critical role of LNK in controlling expression pattern overlapped with that of CD34, suggesting that self-renewal and quiescence of HSCs.20–24 LNK-deficient mice LNK might be involved in hematopoietic cell development from have a 10–15-fold increase in HSC numbers with enhanced endothelial precursors. In addition in endothelial cells, the multi-lineage repopulation after bone marrow (BM) transplanta- proinflammatory cytokine tumor necrosis factor-a, through a tion. LNK constrains quiescence and self-renewal of HSCs/ phosphatidylinositol 3-kinase-dependent signaling pathway, hematopoietic progenitor cell (HPCs), predominantly through rapidly phosphorylates and subsequently upregulates LNK.32 thrombopoietin/JAK2 signaling. LNK-deficient mice also display a In turn, LNK negatively regulates tumor necrosis factor signaling. 3–5-fold increase in circulating white blood cells and platelets, as Adhesion and migration of endothelial cells is also affected well as accumulation of erythroid and megakaryocytes cells by LNK. Following b1-integrin activation, LNK is rapidly phospho-
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