TABLE 2.
STAT3 functions and perturbations causing disease
| Function | Localization: Modification | Activation/Repression Overall Role of STAT3 | Perturbation Leading to Disease | Suggested Intervention | Stage of Drug Development |
|---|---|---|---|---|---|
| Emergency granulopoiesis | N: pY, U | STAT3 positively regulates granulocytic progenitor proliferation, neutrophil release, and chemotaxis during emergency granulopoeisis following microbial infection (Hillmer et al., 2016) | STAT3 AD-HIES patients, having diminished STAT3 activity from AD-LOF STAT3 mutations, show neutrophil-migration impairments and increased risks of skin and lung infections (Zhang et al., 2010) | Augmentation | Preclinical |
| Platelet function | C: pY | Constitutive JAK3/STAT3, essential for platelet function. Pretreating platelets with JAK3i WHI-P131 ↓pY-STAT1/pY-STAT3 and platelet activation | Treatment of mice with Jak3i, WHI-P131 prolonged bleeding time and improved event-free survival in a mouse model of thromboplastin-induced generalized and fatal thromboembolism (Tibbles et al., 2001) | Inhibition | Preclinical |
| N: pY | IL-21/Jak3/STAT3 helps generation of megakaryocytes from CD34+ cells | IL-9/JAK2/STAT3 helps platelet function, promoting development of DVT (Feng et al., 2018) | Inhibition | Preclinical | |
| N: pY | STAT3-regulated TPO, through Jak2-pYSTAT3–mediated transcription, promotes platelet formation from megakaryocytes | Targeting JAK/STAT3 signaling could be an emerging strategy in the management of platelet-associated diseases | Inhibition | Preclinical | |
| C: pY | Collagen induces pYSTAT3 dimer-Syk-PLCγ2 complex, which accelerates catalytic interaction between the collagen-activated (phosphorylated) Syk and its substrate PLCγ2, thereby facilitating platelet activation, calcium mobilization, and aggregation, through hydrolysis of PIP2 to IP3 to mobilize calcium (Zhou et al., 2013) | This nontranscriptional STAT3 function enhances collagen-induced signaling in platelets, potentially making platelets hyperactive in conditions of inflammation, e.g., coronary artery diseases by linking proinflammatory cytokine signals to hemostasis/thrombosis. Repurposed STAT3i, piperlongumine-inhibited collagen-induced platelet activation, aggregation, and thrombus formation by blocking JAK2-STAT3 phosphorylation, reducing the pYSTAT3 dimer-Syk-PLCγ2 complex formation (Yuan et al., 2015a) | Inhibition | Preclinical | |
| DC function | N: pY | Flt3L-STAT3-Tcf4 positively regulates immature pDC and conventional DC development and functions, but activated STAT3 blocks DC maturation in cancer | Sustained IL-6/IL-10 activity in cancer could lead to more tolerogenic iDCs, contributing to loss of immune surveillance phenotype | Inhibition | Preclinical |
| Augmented LIF-STAT3 activity in DC prevents allogeneic transplant rejection (Barton, 2006) | Augmentation | Preclinical | |||
| Macrophage functions | N: pY | IL-10/STAT3 anti-inflammatory role in macrophages through suppression of TLR-NF-κB/MAPK axis (El Kasmi et al., 2007) | STAT3 AD-HIES patients with STAT LOF mutations, display ↑basal/TLR4-mediated proinflammatory cytokines in neutrophils and mononuclear cells (Holland et al., 2007) and severely impaired IL-10 responses | Augmentation | Preclinical |
| B cell functions | N: pY | STAT3- Flt3L promotes transition of Flt3+ pre-pro-B cell HPCs to subsequent precursors, e.g., CLPs (Chou et al., 2006) | Leptin/JAK2/STAT3 stimulates B cells to induce proinflammatory IL-6, TNF-α in obese individuals exacerbating adipose tissue inflammation and insulin resistance | Inhibition | Preclinical |
| N: pY | IL-21/STAT3-Blimp1 helps differentiation of later stage B-lineage–committed CD19+ precursors to IgG-secreting plasma cells | Naive B cells from AD-HIES patients fail to differentiate into antibody-secreting cells when activated with CD40L and IL-21 (Rincon and Pereira, 2018) | Augmentation | Preclinical | |
| CD4+ T cell function | N: pY, pS | IL-6/STAT3-mediated T cell survival independent of Bcl-2 | IL-6/STAT3-mediated resistance to apoptosis of lamina propria CD4+ T cells perpetuates IBD (Atreya et al., 2000) | Inhibition | Clinical |
| IL-6/TGF-β/IL-21 and IL-23/STAT3 mediate Th17 differentiation | Higher morbidity/mortality in ∼10% of asthma patients refractory to steroid treatment show Th17-driven phenotype (2000; McKinley et al., 2008; Al-Ramli et al., 2009) | Inhibition | Preclinical | ||
| N, pS | Cdk5-pS-STAT3 inhibits generation of CD4+ Treg from naive CD4+ precursors by suppressing Treg-specifying transcription factor Foxp3 in mature Tregs (Lam et al., 2015) | In the setting of GVHD, STAT3 deficiency promotes inducible Treg generation, restrains GVHD, and improves survival, suggesting that STAT3 blockade in CD4+ T cells may be useful in treating GVHD | Inhibition | Preclinical | |
| N: pY | STAT3, Foxp3 coregulate IL-10 in Tregs, maintaining ability of Foxp3+ Tregs to inhibit inflammatory Th17 cells | STAT3-HDAC6 transcriptionally ↑IL-10, preventing effective Ag-specific CD4+ T activation in tumor-bearing mice (Cheng et al., 2014), while using an HDACi, ↑effective T cell priming and antitumor response (Wang et al., 2011a; Cheng et al., 2014) | Inhibition | Preclinical | |
| CD8+ T cell function | N: pY | IL-10/IL-21/STAT3-Eomes/BCL6/Blimp1 helps generate stable, long-lived memory CD8+ T cells | STAT3 AD-HIES have ↓memory CD8+ T cells and memory CD4+ T cells, relative to healthy controls, impairing their ability to manage chronic infections | Augmentation | Preclinical |
| N, mt: pY, pS | IL-6/pY-STAT3 helps early transcription of IL-4/IL-21 in CD4 cells (Yang and Rincon, 2016); mtSTAT3 contributes to maintain their late expression through increases in mitochondrial Ca2+ levels and ATP (Yang et al., 2015b) | ||||
| Anaphylaxis | N, mt: pS | Clinical food allergy and anaphylaxis are decreased in AD-HIES patients due to defective mast cell degranulation and reduced endothelial cell permeability (Siegel et al., 2013; Hox et al., 2016), indicating a role of STAT3 in the positive regulation of these processes. STAT3 regulates endothelial permeability downstream of the proinflammatory cytokines IL-6 and TNF-α (Alsaffar et al., 2016) | Vascular inflammation–mediated endothelial STAT3 activation increases vascular leakage through downregulating tight junction proteins (Yun et al., 2017). mt-STAT3 is essential for immune-mediated degranulation of mast cells and basophils, thus making it a candidate for blocking in any allergy scenario (Erlich et al., 2014) | Inhibition | Preclinical |
| Lipid metabolism | N, Mt: pY, pS | Leptin-LepRb-Jak2-STAT3 regulates energy homeostasis, glucose and lipid metabolism, and immune function | Leptin-STAT3 causes immune aging, tumor progression, and PD1/PDL-mediated T cell dysfunction in obese cancer patients, making them better suited to PD1/PDL1-targeted immunotherapy (Wang et al., 2019) | Inhibition | Preclinical |
| N: pY, pS | STAT3-C/EBP/PPARγ regulates adipogenesis from preadipocytes. PPARγ agonist reverses STAT3 inhibition–induced adipogenesis | ||||
| N, Mt: pY, pS | Adipocyte-specific STAT3-KO mice have ↑body weight, ↑adipose tissue mass, but not adipocyte hyperplasia, hyperphagia, or reduced energy expenditure, implicating STAT3 in lipolysis, through ↑ATGL expression, ↓fatty acid synthase, ↓acetyl-CoA carboxylase, ↓AOX | CLL cells adopt to oxidize FFA with constitutively pS-STAT3, which transcriptionally upregulates LPL, which catalyzes the hydrolysis of triglycerides into FFA (Rozovski et al., 2015), making targeting STAT3 a viable strategy to kill CLL cells | Inhibition | Preclinical | |
| Glycometabolism | N, mt: pY, pS | Insulin/IL-6/pYSTAT3 ↓gluconeogenic genes, e.g., G6Pase and PEPCK (Inoue et al., 2004), thus maintaining glucose homeostasis by adjusting glucose production as per energy balance (Inoue, 2016) | Prolonged IL-6 exposure under chronic inflammation leads to insulin resistance and glucose intolerance in human adipocytes, hepatocytes (Gurzov et al., 2016), and skeletal muscles. Blocking IL-6 in diet-induced obese mice represses hepatic inflammation via inhibition of the IL-6/JAK2/STAT3 pathway (Park et al., 2010), thereby increasing insulin sensitivity and resultantly decreasing diet-induced obesity (Priceman et al., 2013) | Inhibition | Preclinical |
| The leptin-JAK2/STAT3 pathway inhibits insulin synthesis, whereas SOCS3 blocks the STAT3-dependent regulation of pre-proinsulin 1 gene | |||||
| RS | N, mt: pY, pS | Activated by RS. Protects from IR and non-IR, e.g., UV-induced cell death | Chronic UV- mediated STAT3 activation key step in UV-induced skin cancer | Inhibition | Clinical |
| OS | N, mt: pY, pS, Ac | Both activated and repressed by OS. Activation seems to be protected from ROS-mediated damage | Asbestos, cigarette smoke–activated pY-STAT3 protects cells from ROS-mediated apoptosis, leading to carcinogenesis | Inhibition | Clinical |
| pY-STAT3 protects from hyperoxia-induced acute lung injury resulting from increasing O2, used to treat lung failure, e.g., ARDS | Augment | Preclinical | |||
| GS | N, mt: pY, pS | Activated by GS. Augments DNA repair genes, e.g., MDC1-ATm-chk2 pathway helping in DNA repair and cell protection | Cancer cells escape IR through upregulation of pY-STAT3 that protects from IR leading to radio- or chemoresistance, e.g., HNSCC | Inhibition | Preclinical |
| Senescence | N, mt: pY, pS | JAK-STAT3 promotes replicative (Kojima et al., 2005) and oncogene-induced senescence (Kuilman et al., 2008) | Senescence is implicated in age-related diseases, including renal dysfunction, T2D, IPF, cardiovascular disease, and age-related cachexia (McHugh and Gil, 2018), suggesting use of STAT inhibition as therapy | Inhibition | Preclinical |
| IL-6/STAT3 activated by chemotherapy promoted drug-induced premature senescence in autocrine manner to help maintain a minimal residual tumor burden that could lead to relapse (Gilbert and Hemann, 2010) | Inhibition | Preclinical | |||
| Autophagy | N, mt: pY, pS | Nuclear STAT3 can be both proautophagic, e.g., LIF/STAT3 in mammary glandular cells through ↑PIK3R1/p55α and PIK3R1/p50α (Pensa et al., 2014) or antiautophagic through ↑antiautophagy-related genes, e.g., BCL2, BCL2L1, and MCL1 (Fukada et al., 1996; Bromberg et al., 1999; Bowman et al., 2000) | STAT3 increased autophagy in mouse models of cancer cachexia (Penna et al., 2013), suggesting inhibition as viable therapy | Inhibition | Preclinical |
| Loss of mtSTAT3, which interacts with complex I/II of the ETC to modulate their activities, results in ↑ROS (Szczepanek et al., 2012), inducing mitophagy (Scherz-Shouval and Elazar, 2007). | mtSTAT3 suppresses autophagy induced by oxidative stress and effectively preserves mitochondria from mitophagy, protecting from ischemia (Szczepanek et al., 2011) | Augment | Preclinical | ||
| Wound healing | N: pY, pS | STAT3 is involved both in the initial inflammatory stages following tissue injury (Dauer et al., 2005) as well as later re-epithelialization stage of wound healing (Sano et al., 1999). Both pY and pS (Shen et al., 2004; Lim et al., 2006; Dunkel et al., 2012) STAT3 involved | Persistently activated STAT3, independently as well as in conjunction with TGF-β, drives unregulated wound healing, leading to fibrosis through overexpression of ECM components, e.g., COL1A2 (Papaioannou et al., 2018), MMPs (Matsui et al., 2017), and promoting apoptosis resistance of fibroblasts (Moodley et al., 2003; Habiel and Hogaboam, 2014; Xu et al., 2014a; Milara et al., 2018), aberrant EMT (Kasembeli et al., 2018), etc. | Inhibition | Clinical |
Ac, acetylation; AOX, acyl-CoA oxidase; ARDS, adult respiratory distress syndrome; ATGL, adipose triglyceride lipase; C, cytoplasmic; COL1A2, collagen type I alpha 2 chain; CLP, common lymphoid progenitor; DVT, deep venous thrombosis; EMT, epithelial to mesenchymal transition; FFA, free fatty acids; FLT3L, FMS-like tyrosine kinase 3 ligand; G6Pase, glucose-6-phosphatase; GS, genotoxic stress; HPCs, hematopoietic progenitor cells; iDC, immature DC; IP3, inositol 1,4,5-triphosphate; IPF, idiopathic pulmonary fibrosis; LIF, leukemia inhibitory factor; LPL, lipoprotein lipase; N, nuclear; LOF, loss of function; OS, oxidative stress; pDC, plasmacytoid DC; PDC, pyruvate dehydrogenase complex; PEPCK, phosphoenolpyruvate carboxykinase; PIP2, phosphatidylinositol 4,5-bisphosphate; pS, pS727; pY, pY705; RS, radiation stress; T2D, type 2 diabetes; TPO, thrombopoietin.