Signal-transducing adaptor protein-1 and protein-2 in hematopoiesis and diseases
2021; Elsevier BV; Volume: 105; Linguagem: Inglês
10.1016/j.exphem.2021.11.002
ISSN1873-2399
AutoresMichiko Ichii, Kenji Oritani, Jun Toda, Naoki Hosen, Tadashi Matsuda, Yuzuru Kanakura,
Tópico(s)Cytokine Signaling Pathways and Interactions
Resumo•Inflammatory and immune signaling affects hematopoiesis under stress and malignant pathogenesis in bone marrow.•STAPs have critical roles in the modulation of intracellular signaling cascades.•STAPs in bone marrow are involved in the proliferation of stressed B progenitors and CML stem cells. Inflammatory and immune signals are involved in stressed hematopoiesis under myeloablation, infection, chronic inflammation, and aging. These signals also affect malignant pathogenesis, and the dysregulated immune environment which causes the resistance to treatment. On activation, various types of protein tyrosine kinases in the cytoplasm mediate the cascade, leading to the transcription of target genes in the nucleus. Adaptor molecules are commonly defined as proteins that lack enzymatic activity, DNA-binding or receptor functions and possess protein–protein or protein–lipid interaction domains. By binding to specific domains of signaling molecules, adaptor proteins adjust the signaling responses after the ligation of receptors of soluble factors, including cytokines, chemokines, and growth factors, as well as pattern recognition receptors such as toll-like receptors. The signal-transducing adaptor protein (STAP) family regulates various intracellular signaling pathways. These proteins have a pleckstrin homology domain in the N-terminal region and an SRC-homology 2-like domain in the central region, representing typical binding structures as adapter proteins. Following the elucidation of the effects of STAPs on terminally differentiated immune cells, such as macrophages, T cells, mast cells, and basophils, recent findings have indicated the critical roles of STAP-2 in B-cell progenitor cells in marrow under hematopoietic stress and STAP-1 and -2 in BCR-ABL-transduced leukemogenesis. In this review, we focus on the role of STAPs in the bone marrow. Inflammatory and immune signals are involved in stressed hematopoiesis under myeloablation, infection, chronic inflammation, and aging. These signals also affect malignant pathogenesis, and the dysregulated immune environment which causes the resistance to treatment. On activation, various types of protein tyrosine kinases in the cytoplasm mediate the cascade, leading to the transcription of target genes in the nucleus. Adaptor molecules are commonly defined as proteins that lack enzymatic activity, DNA-binding or receptor functions and possess protein–protein or protein–lipid interaction domains. By binding to specific domains of signaling molecules, adaptor proteins adjust the signaling responses after the ligation of receptors of soluble factors, including cytokines, chemokines, and growth factors, as well as pattern recognition receptors such as toll-like receptors. The signal-transducing adaptor protein (STAP) family regulates various intracellular signaling pathways. These proteins have a pleckstrin homology domain in the N-terminal region and an SRC-homology 2-like domain in the central region, representing typical binding structures as adapter proteins. Following the elucidation of the effects of STAPs on terminally differentiated immune cells, such as macrophages, T cells, mast cells, and basophils, recent findings have indicated the critical roles of STAP-2 in B-cell progenitor cells in marrow under hematopoietic stress and STAP-1 and -2 in BCR-ABL-transduced leukemogenesis. In this review, we focus on the role of STAPs in the bone marrow. A variety of factors contribute to the generation of blood cells [1Haas S Trumpp A Milsom MD. Causes and consequences of hematopoietic stem cell heterogeneity.Cell Stem Cell. 2018; 22: 627-638Abstract Full Text Full Text PDF PubMed Scopus (170) Google Scholar,2Laurenti E Gottgens B. From haematopoietic stem cells to complex differentiation landscapes.Nature. 2018; 553: 418-426Crossref PubMed Scopus (408) Google Scholar]. Hematopoiesis in the bone marrow (BM) is regulated by the cell-intrinsic properties of hematopoietic stem/progenitor cells (HSPCs) at each differentiation stage. Furthermore, cell-extrinsic mechanisms arise from the condition of the microenvironment, which includes various cellular components, such as hematopoietic, endothelial, mesenchymal and neural lineage cells, oxygen level, and concentration of soluble factors [1Haas S Trumpp A Milsom MD. Causes and consequences of hematopoietic stem cell heterogeneity.Cell Stem Cell. 2018; 22: 627-638Abstract Full Text Full Text PDF PubMed Scopus (170) Google Scholar, 2Laurenti E Gottgens B. From haematopoietic stem cells to complex differentiation landscapes.Nature. 2018; 553: 418-426Crossref PubMed Scopus (408) Google Scholar, 3Mendez-Ferrer S Bonnet D Steensma DP et al.Bone marrow niches in haematological malignancies.Nat Rev Cancer. 2020; 20: 285-298Crossref PubMed Scopus (203) Google Scholar]. Cytokines, growth factors and chemokines, such as granulocyte colony-stimulating factor (G-CSF), macrophage colony-stimulating factor (M-CSF), granulocyte–macrophage colony-stimulating factor (GM-CSF), stem cell factor (SCF, also known as Kit ligand), FMS-like tyrosine kinase 3 (Flt3) ligand, interleukin (IL)-7, erythropoietin (EPO), thrombopoietin and CXCL12, were identified from the 1960s to the 1990s. At present, their critical roles in the differentiation, proliferation, survival, and mobilization of HSPCs are well known [4Ward AC Touw I Yoshimura A. The Jak–Stat pathway in normal and perturbed hematopoiesis.Blood. 2000; 95: 19-29Crossref PubMed Google Scholar, 5Rane SG JAKs Reddy EP. STATs and Src kinases in hematopoiesis.Oncogene. 2002; 21: 3334-3358Crossref PubMed Scopus (205) Google Scholar, 6Kuhrt D Wojchowski DM. Emerging EPO and EPO receptor regulators and signal transducers.Blood. 2015; 125: 3536-3541Crossref PubMed Scopus (114) Google Scholar]. The binding of receptors on HSPCs to their specific ligands activates the intracellular signaling cascade, resulting in transcriptional responses. Cytokines and growth factors also have pleiotropic roles in the immune response, neurogenesis, embryogenesis, and oncogenesis. It is interesting that a particular cytokine can induce a variety of biological functions on various tissues and cells. In addition, several different cytokines sometimes have overlapping effects on the same cell type. On ligation, signal transduction proteins, such as Src, Janus kinase (JAK) tyrosine kinase, signal transducer and activator of transcription (STAT), Smad, mitogen-activated protein kinase (MAPK), and phosphatidylinositol 3-kinase (PI3-K), are activated through distinct regions of each receptor's cytoplasmic domain [4Ward AC Touw I Yoshimura A. The Jak–Stat pathway in normal and perturbed hematopoiesis.Blood. 2000; 95: 19-29Crossref PubMed Google Scholar,7O'Shea JJ and Plenge R.JAK STAT signaling molecules in immunoregulation and immune-mediated disease.Immunity. 2012; 36: 542-550Abstract Full Text Full Text PDF PubMed Scopus (799) Google Scholar]. While the receptors usually mediate the signals by inducing the phosphorylation of tyrosine residues, some cytokine receptors that lack intrinsic tyrosine kinase activity are coupled to the JAK family and their substrates, STAT proteins. These protein tyrosine kinases (PTKs) phosphorylate various intracellular or transmembrane adaptors and enzymes, leading to transcriptional activation [8Rhee I Veillette A. Protein tyrosine phosphatases in lymphocyte activation and autoimmunity.Nat Immunol. 2012; 13: 439-447Crossref PubMed Scopus (195) Google Scholar]. During the 20th century, studies on the effects on immune and inflammatory responses with terminally differentiated immune blood cells and on hematopoiesis in BM were conducted separately. However, in 2006, Nagai et al. [9Esplin BL Shimazu T Welner RS et al.Chronic exposure to a TLR ligand injures hematopoietic stem cells.J Immunol. 2011; 186: 5367-5375Crossref PubMed Scopus (243) Google Scholar] reported that toll-like receptors (TLRs), which recognize microbial or viral pathogens, are expressed on HSPCs, and the ligation is involved in the cell cycle and myeloid differentiation. Accumulating evidence has indicated that signal transduction through immune and inflammatory responses via the receptor of several pro-inflammatory cytokines, including IL-1, IL-6, tumor necrosis factor (TNF)-α, and transforming growth factor (TGF)-β, as well as pattern recognition receptors such as TLRs affect the proliferation and lineage development of HSPCs during hematopoietic stress conditions (i.e., infection, aging, irradiation, hematopoietic stem cell [HSC] transplantation and cytotoxic chemotherapy) [10Chavakis T Mitroulis I Hajishengallis G. 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Inflammation: a key regulator of hematopoietic stem cell fate in health and disease.Blood. 2017; 130: 1693-1698Crossref PubMed Scopus (232) Google Scholar]. The stimulation from extracellular molecules, such as cytokines and chemokines, via membrane receptor is not a simple "on–off" or "one-on-one" reaction. The regulation of signal transduction cascades by adaptor molecules can fine-tune the magnitude, duration, and types of induced transcriptional responses after ligation. This review focuses on the role of the signal-transducing adaptor protein (STAP) family in BM. The mechanism by which PTKs and the involved pathways are activated and cross talk depends on the cell type, developmental state, and environmental conditions. One of the important mechanisms is regulation by adaptor molecules. Although adaptor proteins lack enzymatic activity, DNA-binding, or receptor functions, they possess protein–protein or protein–lipid interaction domains, such as Src homology (SH) 2 and SH3, or pleckstrin homology (PH) domains, which bind specific motifs or sequences of the linking partner molecules and spread the larger signaling responses [17Kurosaki T. Regulation of B-cell signal transduction by adaptor proteins.Nat Rev Immunol. 2002; 2: 354-363Crossref PubMed Scopus (176) Google Scholar, 18Jordan MS Singer AL Koretzky GA. Adaptors as central mediators of signal transduction in immune cells.Nat Immunol. 2003; 4: 110-116Crossref PubMed Scopus (224) Google Scholar, 19Koretzky GA Myung PS. Positive and negative regulation of T-cell activation by adaptor proteins.Nat Rev Immunol. 2001; 1: 95-107Crossref PubMed Scopus (122) Google Scholar]. A member of the STAP family, STAP-1, was cloned as a c-Kit-interacting protein by yeast two-hybrid screening with a murine HSC library in 2000 [20Masuhara M Nagao K Nishikawa M Sasaki M Yoshimura A Osawa M. Molecular cloning of murine STAP-1, the stem-cell-specific adaptor protein containing PH and SH2 domains.Biochem Biophys Res Commun. 2000; 268: 697-703Crossref PubMed Scopus (35) Google Scholar]. By use of the same method, STAP-2 was subsequently identified as a protein that interacted with M-CSF receptor (M-CSFR) from a complementary DNA library of the murine fetal liver in 2003 [21Minoguchi M Minoguchi S Aki D et al.STAP-2/BKS, an adaptor/docking protein, modulates STAT3 activation in acute-phase response through its YXXQ motif.J Biol Chem. 2003; 278: 11182-11189Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar]. These proteins have PH domains in the N-terminal region and SH2-like domains in the central region, representing typical structures of adapter proteins. PH domains are known to mediate the translocation to the plasma membrane with recognition of the specific phosphoinositides in the phospholipids (Figure 1). SH2 binds specific phosphotyrosine (pY)-containing motifs in the context of three to six amino acids located at the carboxy terminal to the pY, providing specificity. The YXXQ motif required for STAT3 activation has been detected in a proline-rich region in STAP-2. The genomic sequence of STAP-2 contains several potential binding sites for c-Rel, AP-1, p65/nuclear factor (NF)-κB, and STAT proteins in the 5′ region [21Minoguchi M Minoguchi S Aki D et al.STAP-2/BKS, an adaptor/docking protein, modulates STAT3 activation in acute-phase response through its YXXQ motif.J Biol Chem. 2003; 278: 11182-11189Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar]. As the adaptor protein structure predicts, the interaction with several tyrosine phosphorylated proteins, including inhibitor of nuclear factor-κB (IκB) kinase complex, STAT3, STAT5, Vav1, and MyD88 in inflammatory/immune response and tumorigenesis has been reported (Table 1) [22Matsuda T Oritani K. STAP-2 adaptor protein regulates multiple steps of immune and inflammatory responses.Biol Pharm Bull. 2021; 44: 895-901Crossref PubMed Scopus (8) Google Scholar]. There are no reports on the interactions between STAPs and other adopter proteins, so far. The human homologue of STAP-1, also known as BCR downstream signaling 1 (BRDG1), binds to cKit and Tec, which phosphorylates STAP-1 directly and activates the response to B-cell receptor (BCR) stimulation [23Ohya K Kajigaya S Kitanaka A et al.Molecular cloning of a docking protein, BRDG1, that acts downstream of the Tec tyrosine kinase.Proc Natl Acad Sci USA. 1999; 96: 11976-11981Crossref PubMed Scopus (50) Google Scholar]. The human homologue of STAP-2, also known as BKS, is a substrate of breast tumor kinase (Brk), whose tyrosine residues are phosphorylated by Brk, expressed in breast, colon, prostate, and skin cancer cells [24Mitchell PJ Barker KT Martindale JE et al.Cloning and characterisation of cDNAs encoding a novel non-receptor tyrosine kinase, brk, expressed in human breast tumours.Oncogene. 1994; 9: 2383-2390PubMed Google Scholar, 25Easty DJ Mitchell PJ Patel K Flørenes VA Spritz RA Bennett DC. Loss of expression of receptor tyrosine kinase family genes PTK7 and SEK in metastatic melanoma.Int J Cancer. 1997; 71: 1061-1065Crossref PubMed Scopus (113) Google Scholar, 26Barker KT Jackson LE Crompton MR. BRK tyrosine kinase expression in a high proportion of human breast carcinomas.Oncogene. 1997; 15: 799-805Crossref PubMed Scopus (135) Google Scholar, 27Ikeda O Sekine Y Mizushima A et al.Interactions of STAP-2 with Brk and STAT3 participate in cell growth of human breast cancer cells.J Biol Chem. 2010; 285: 38093-38103Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar, 28Ikeda O Mizushima A Sekine Y et al.Involvement of STAP-2 in Brk-mediated phosphorylation and activation of STAT5 in breast cancer cells.Cancer Sci. 2011; 102: 756-761Crossref PubMed Scopus (26) Google Scholar, 29Sekine Y Togi S Muromoto R et al.STAP-2 protein expression in B16F10 melanoma cells positively regulates protein levels of tyrosinase, which determines organs to infiltrate in the body.J Biol Chem. 2015; 290: 17462-17473Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar, 30Kitai Y Iwakami M Saitoh K et al.STAP-2 protein promotes prostate cancer growth by enhancing epidermal growth factor receptor stabilization.J Biol Chem. 2017; 292: 19392-19399Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar].Table 1Functions of STAPs in hematopoietic cells and diseasesCell typeSTAPBindingmoleculeAffected molecule/signalFunctionRefs.MacrophageSTAP-2M-CSFRM-CSFRMigration, wound-healing21,37,38STAP-2MyD88, IKK-α/βTLR4, NF-κB, MAPKProduction of IL-6 and TNFα21,48MicrogliaSTAP-1M-CSFRM-CSFR33T cellSTAP-2FAKIntegrinAdhesion to fibronectin39STAP-2Vav1, Pyk2Vav1/Rac1Chemotaxis40,42STAP-2FADD, caspase-8FasApoptosis41Memory CD8+ T cellSTAP-2STAT5Long-term maintenance45ThymocyteSTAP-2STAT5IL-2RProliferation43B progenitorSTAP-2MAPK/p38Apoptosis73Mast cellSTAP-2FcεRIPLC-γ2Ca mobilization, degranulation46BasophilSTAP-2FcεRILyn, PLC-γ2Production of IL-4 and IL-647iNKT cellSTAP-1Akt, Erk, p38Production of IL-4 and IFN32CML stem cellSTAP-1BCR-ABL, STAT5BCR-ABL, JAK2, PPARγApoptosis74,89CML cellSTAP-2BCR-ABLBCR-ABL, STAT5, ErkProliferation, migration82,83v-ABL-transformed B cellSTAP-1ABL, mTORDrug resistance81FADD=Fas-associated death domain protein; FAK=focal adhesion kinase; IFN=interferon; IKK=inhibitor of nuclear factor-κ B; iNKT=invariant natural killer T; JAK=Janus kinase; M-CSFR=macrophage colony-stimulating factor receptor; MAPK=mitogen-activated protein kinase; NF-κB=nuclear factor-κB; PLC=phospholipase C; PPAR=peroxisome proliferator-activated receptor; STAP=signal-transducing adaptor protein; STAT=signal transducer and activator of transcription; TLR=toll-like receptor; TNF=tumor necrosis factor. Open table in a new tab FADD=Fas-associated death domain protein; FAK=focal adhesion kinase; IFN=interferon; IKK=inhibitor of nuclear factor-κ B; iNKT=invariant natural killer T; JAK=Janus kinase; M-CSFR=macrophage colony-stimulating factor receptor; MAPK=mitogen-activated protein kinase; NF-κB=nuclear factor-κB; PLC=phospholipase C; PPAR=peroxisome proliferator-activated receptor; STAP=signal-transducing adaptor protein; STAT=signal transducer and activator of transcription; TLR=toll-like receptor; TNF=tumor necrosis factor. Elucidation of the effects of STAPs in BM was preceded by studies on their role in terminally differentiated immune cells (Table 1). Using a mouse model, we determined that STAP-1 affects the severity of autoimmune hepatitis by reducing the secretion of IL-4 and interferon-γ by invariant natural killer T cells [31Kashiwakura JI Saitoh K Ihara T et al.Expression of signal-transducing adaptor protein-1 attenuates experimental autoimmune hepatitis via down-regulating activation and homeostasis of invariant natural killer T cells.PLoS One. 2020; 15e0241440Crossref PubMed Scopus (4) Google Scholar]. Stoecker et al. [32Stoecker K Weigelt K Ebert S Karlstetter M Walczak Y Langmann T. Induction of STAP-1 promotes neurotoxic activation of microglia.Biochem Biophys Res Commun. 2009; 379: 121-126Crossref PubMed Scopus (17) Google Scholar] reported that STAP-1 regulates microglia activation in the retinoschisin-deficient mouse retina through inhibition of the M-CSFR signaling. Although clinical studies reported upregulated expression of STAP-1 in peripheral blood mononuclear cells from multiple sclerosis patients receiving subcutaneous interferon-β-1a, eosinophilic sputa in chronic obstructive pulmonary disease patients, and the airway epithelium from asthma patients, the role of STAP-1 in these pathogeneses remains unknown [33Hecker M Hartmann C Kandulski O et al.Interferon-beta therapy in multiple sclerosis: The short-term and long-term effects on the patients' individual gene expression in peripheral blood.Mol Neurobiol. 2013; 48: 737-756Crossref PubMed Scopus (27) Google Scholar, 34Singh D Bassi M Balzano D et al.COPD patients with chronic bronchitis and higher sputum eosinophil counts show increased type-2 and PDE4 gene expression in sputum.J Cell Mol Med. 2021; 25: 905-918Crossref PubMed Scopus (9) Google Scholar, 35Bazan-Socha S Buregwa-Czuma S Jakiela B et al.Reticular basement membrane thickness is associated with growth- and fibrosis-promoting airway transcriptome profile-study in asthma patients.Int J Mol Sci. 2021; 22: 998Crossref PubMed Scopus (13) Google Scholar]. With respect to STAP-2, various roles in macrophages, T cells, mast cells, and basophils have been reported [21Minoguchi M Minoguchi S Aki D et al.STAP-2/BKS, an adaptor/docking protein, modulates STAT3 activation in acute-phase response through its YXXQ motif.J Biol Chem. 2003; 278: 11182-11189Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar,22Matsuda T Oritani K. STAP-2 adaptor protein regulates multiple steps of immune and inflammatory responses.Biol Pharm Bull. 2021; 44: 895-901Crossref PubMed Scopus (8) Google Scholar,36Ikeda O Sekine Y Kakisaka M et al.STAP-2 regulates c-Fms/M-CSF receptor signaling in murine macrophage Raw 264.7 cells.Biochem Biophys Res Commun. 2007; 358: 931-937Crossref PubMed Scopus (14) Google Scholar, 37Ikeda O Sekine Y Muromoto R Ohbayashi N Yoshimura A Matsuda T. Enhanced c-Fms/M-CSF receptor signaling and wound-healing process in bone marrow-derived macrophages of signal-transducing adaptor protein-2 (STAP-2) deficient mice.Biol Pharm Bull. 2008; 31: 1790-1793Crossref PubMed Scopus (11) Google Scholar, 38Cho SSL Han J James SJ et al.Dual-specificity phosphatase 12 targets p38 MAP kinase to regulate macrophage response to intracellular bacterial infection.Front Immunol. 2017; 8: 1259Crossref PubMed Scopus (27) Google Scholar, 39Sekine Y Tsuji S Ikeda O et al.Signal-transducing adaptor protein-2 regulates integrin-mediated T cell adhesion through protein degradation of focal adhesion kinase.J Immunol. 2007; 179: 2397-2407Crossref PubMed Scopus (46) Google Scholar, 40Sekine Y Ikeda O Tsuji S et al.Signal-transducing adaptor protein-2 regulates stromal cell-derived factor-1 alpha-induced chemotaxis in T cells.J Immunol. 2009; 183: 7966-7974Crossref PubMed Scopus (26) Google Scholar, 41Sekine Y Yamamoto C Kakisaka M et al.Signal-transducing adaptor protein-2 modulates Fas-mediated T cell apoptosis by interacting with caspase-8.J Immunol. 2012; 188: 6194-6204Crossref PubMed Scopus (17) Google Scholar, 42Saitoh K Tsuchiya T Kashiwakura JI et al.STAP-2 interacts with Pyk2 and enhances Pyk2 activity in T-cells.Biochem Biophys Res Commun. 2017; 488: 81-87Crossref PubMed Scopus (7) Google Scholar, 43Sekine Y Yamamoto T Yumioka T et al.Physical and functional interactions between STAP-2/BKS and STAT5.J Biol Chem. 2005; 280: 8188-8196Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar, 44Saito H Ichii M Toda J et al.Graft-versus-host disease develops in mice transplanted with lymphocyte-depleted bone marrow cells from signal-transducing adaptor protein-2 transgenic mice.Biochem Biophys Res Commun. 2021; 537: 118-124Crossref PubMed Scopus (2) Google Scholar, 45Muraoka D Seo N Hayashi T et al.Signal-transducing adaptor protein-2 promotes generation of functional long-term memory CD8+ T cells by preventing terminal effector differentiation.Oncotarget. 2017; 8: 30766-30780Crossref PubMed Scopus (8) Google Scholar, 46Sekine Y Nishida K Yamasaki S et al.Signal-transducing adaptor protein-2 controls the IgE-mediated, mast cell-mediated anaphylactic responses.J Immunol. 2014; 192: 3488-3495Crossref PubMed Scopus (13) Google Scholar, 47Kashiwakura JI Yamashita S Yoshihara M et al.STAP-2 positively regulates FcεRI-mediated basophil activation and basophil-dependent allergic inflammatory reactions.Int Immunol. 2019; 31: 349-356Crossref PubMed Scopus (7) Google Scholar]. Some of these functions have been confirmed using mouse disease models, such as lipopolysaccharide (LPS) sepsis, graft-versus-host disease (GVHD), vaccination, and IgE-associated allergic inflammation models [21Minoguchi M Minoguchi S Aki D et al.STAP-2/BKS, an adaptor/docking protein, modulates STAT3 activation in acute-phase response through its YXXQ motif.J Biol Chem. 2003; 278: 11182-11189Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar,22Matsuda T Oritani K. STAP-2 adaptor protein regulates multiple steps of immune and inflammatory responses.Biol Pharm Bull. 2021; 44: 895-901Crossref PubMed Scopus (8) Google Scholar,44Saito H Ichii M Toda J et al.Graft-versus-host disease develops in mice transplanted with lymphocyte-depleted bone marrow cells from signal-transducing adaptor protein-2 transgenic mice.Biochem Biophys Res Commun. 2021; 537: 118-124Crossref PubMed Scopus (2) Google Scholar, 45Muraoka D Seo N Hayashi T et al.Signal-transducing adaptor protein-2 promotes generation of functional long-term memory CD8+ T cells by preventing terminal effector differentiation.Oncotarget. 2017; 8: 30766-30780Crossref PubMed Scopus (8) Google Scholar, 46Sekine Y Nishida K Yamasaki S et al.Signal-transducing adaptor protein-2 controls the IgE-mediated, mast cell-mediated anaphylactic responses.J Immunol. 2014; 192: 3488-3495Crossref PubMed Scopus (13) Google Scholar, 47Kashiwakura JI Yamashita S Yoshihara M et al.STAP-2 positively regulates FcεRI-mediated basophil activation and basophil-dependent allergic inflammatory reactions.Int Immunol. 2019; 31: 349-356Crossref PubMed Scopus (7) Google Scholar]. As mentioned earlier, STAP-2 was originally cloned as an M-CSFR-binding protein [21Minoguchi M Minoguchi S Aki D et al.STAP-2/BKS, an adaptor/docking protein, modulates STAT3 activation in acute-phase response through its YXXQ motif.J Biol Chem. 2003; 278: 11182-11189Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar]. Ectopically expressed STAP-2 downregulates M-CSF-induced pathways, leading to impairment of migration and wound healing via interaction with the PH domain in STAP-2 [21Minoguchi M Minoguchi S Aki D et al.STAP-2/BKS, an adaptor/docking protein, modulates STAT3 activation in acute-phase response through its YXXQ motif.J Biol Chem. 2003; 278: 11182-11189Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar,36Ikeda O Sekine Y Kakisaka M et al.STAP-2 regulates c-Fms/M-CSF receptor signaling in murine macrophage Raw 264.7 cells.Biochem Biophys Res Commun. 2007; 358: 931-937Crossref PubMed Scopus (14) Google Scholar,37Ikeda O Sekine Y Muromoto R Ohbayashi N Yoshimura A Matsuda T. Enhanced c-Fms/M-CSF receptor signaling and wound-healing process in bone marrow-derived macrophages of signal-transducing adaptor protein-2 (STAP-2) deficient mice.Biol Pharm Bull. 2008; 31: 1790-1793Crossref PubMed Scopus (11) Google Scholar]. Interestingly, STAP-2 elevates NF-κB activity and cytokine production on LPS/TLR4 ligation in macrophages [48Sekine Y Yumioka T Yamamoto T et al.Modulation of TLR4 signaling by a novel adaptor protein signal-transducing adaptor protein-2 in macrophages.J Immunol. 2006; 176: 380-389Crossref PubMed Scopus (78) Google Scholar]. Direct binding of both MyD88 and IκB kinase-α/β at the SH2 domain of STAP-2 was confirmed [21Minoguchi M Minoguchi S Aki D et al.STAP-2/BKS, an adaptor/docking protein, modulates STAT3 activation in acute-phase response through its YXXQ motif.J Biol Chem. 2003; 278: 11182-11189Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar]. STAP-2 in macrophages has also been reported to activate MAPK signaling through the interaction between dual-specificity phosphatase (DUSP) 12 and p38 [38Cho SSL Han J James SJ et al.Dual-specificity phosphatase 12 targets p38 MAP kinase to regulate macrophage response to intracellular bacterial infection.Front Immunol. 2017; 8: 1259Crossref PubMed Scopus (27) Google Scholar]. In T cells, STAP-2 regulates the adhesion to fibronectin with focal adhesion kinase (FAK) ubiquitination by the recruitment of c-Cbl and CXCL12-induced chemotaxis via its binding to Vav1 and Pyk2, as well as Fas and caspase-8-mediated apoptosis with direct interaction [39Sekine Y Tsuji S Ikeda O et al.Signal-transducing adaptor protein-2 regulates integrin-mediated T cell adhesion through protein degradation of focal adhesion kinase.J Immunol. 2007; 179: 2397-2407Crossref PubMed Scopus (46) Google Scholar, 40Sekine Y Ikeda O Tsuji S et al.Signal-transducing adaptor protein-2 regulates stromal cell-derived factor-1 alpha-induced chemotaxis in T cells.J Immunol. 2009; 183: 7966-7974Crossref PubMed Scopus (26) Google Scholar, 41Sekine Y Yamamoto C Kakisaka M et al.Signal-transducing adaptor protein-2 modulates Fas-mediated T cell apoptosis by interacting with caspase-8.J Immunol. 2012; 188: 6194-6204Crossref PubMed Scopus (17) Google Scholar, 42Saitoh K Tsuchiya T Kashiwakura JI et al.STAP-2 interacts with Pyk2 and enhances Pyk2 activity in T-cells.Biochem Biophys Res Commun. 2017; 488: 81-87Crossref PubMed Scopus (7) Google Scholar]. The proliferation of thymocytes and the maintenance of long-lived memory CD8+ T cells are promoted by STAP-2 through interaction with STAT signaling [43Sekine Y Yamamoto T Yumioka T et al.Physical and functional interactions between STAP-2/BKS and STAT5.J Biol Chem. 2005; 280: 8188-8196Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar,45Muraoka D Seo N Hayashi T et al.Signal-transducing adaptor protein-2 promotes generation of functional long-term memory CD8+ T cells by preventing terminal effector differentiation.Oncotarget. 2017; 8: 30766-30780Crossref PubMed Scopus (8) Google Scholar]. STAP-2 can also bind to FcεRI, which is expressed in mast cells and basophils [46Sekine Y Nishida K Yamasaki S et al.Signal-transducing adaptor protein-2 controls the IgE-mediated, mast cell-mediated anaphylactic responses.J Immunol. 2014; 192: 3488-3495Crossref PubMed Scopus (13) Google Scholar,47Kashiwakura JI Yamashita S Yoshihara M et al.STAP-
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