Syk Signaling Pathway Research Articles

Tolerability and response of the novel SYK/JAK inhibitor cerdulatinib in a phase 2a study in relapsed/refractory peripheral t cell lymphoma (PTCL).

e19532Background: Pre-clinical data suggest a role for SYK and JAK signaling pathways as oncogenic drivers in PTCL. Most compelling is the frequent demonstration of SYK expression (not expressed in...

Integrin CD11b negatively regulates Mincle-induced signaling via the Lyn\u2013SIRP\u03b1\u2013SHP1 complex

During mycobacteria infection, anti-inflammatory responses allow the host to avoid tissue damage caused by overactivation of the immune system; however, little is known about the negative modulators that specifically control mycobacteria-induced immune responses. Here we demonstrate that integrin CD11b is a critical negative regulator of mycobacteria cord factor-induced macrophage-inducible C-type lectin (Mincle) signaling. CD11b deficiency resulted in hyperinflammation following mycobacterial infection. Activation of Mincle by mycobacterial components turns on not only the Syk signaling pathway but also CD11b signaling and induces formation of a Mincle–CD11b signaling complex. The activated CD11b recruits Lyn, SIRPα and SHP1, which dephosphorylate Syk to inhibit Mincle-mediated inflammation. Furthermore, the Lyn activator MLR1023 effectively suppressed Mincle signaling, indicating the possibility of Lyn-mediated control of inflammatory responses. These results describe a new role for CD11b in fine-tuning the immune response against mycobacterium infection.

Phagocytic Receptors Activate Syk and Src Signaling during Borrelia burgdorferi Phagocytosis.

Phagocytosis of the Lyme disease-causing pathogen Borrelia burgdorferi has been shown to be important for generating an inflammatory response to the pathogen. As a result, understanding the mechanisms of phagocytosis has been an area of great interest in the field of Lyme disease. Several cell surface receptors that participate in B. burgdorferi phagocytosis have been reported, including the scavenger receptor MARCO and integrin α3β1. We sought to define the mechanisms by which these receptors mediate phagocytosis and to identify signaling pathways activated downstream of these receptors upon contact with B. burgdorferi We identified both Syk and Src signaling pathways as ones that participate in B. burgdorferi phagocytosis and the resulting cytokine activation. In our studies, we found that both MARCO and integrin β1 play a role in the activation of the Src kinase pathway. However, only integrin β1 participates in the activation of Syk. Interestingly, the integrin activates Syk without the help of the signaling adaptor Dap12 or FcRγ. Thus, we report that multiple pathways participate in B. burgdorferi internalization and that different cell surface receptors act simultaneously in cooperation and independently to mediate phagocytosis.

Sterile type 2 inflammation triggered by microparticles is abrogated by inhibition of IL33 through blockade of Bruton’s tyrosine kinase

Abstract Wear debris microparticle release associated with total joint arthroplasty may contribute to harmful inflammation, osteolysis and implant failure. We examined the role of different molecular signaling pathways in microparticle-mediated inflammation. Intraperitoneal inoculation of cobalt chrome (CoCr) in mice induced a robust innate type 2 response with increases in IL4, IL5, IL13, IL33, M2 macrophages, eosinophils and neutrophils compared to controls given vehicle only. Blockade of the SYK signaling pathway with the inhibitor BAY 61-3606 or the down stream BTK signaling pathway with Ibrutinib abrogated the CoCr-mediated innate type 2 inflammation. Further studies in CBA/Nxid mice, a genetic BTK loss of function mutant also showed decreases in type 2 inflammation, confirming a critical role for BTK in CoCr mediated sterile type 2 inflammation. Inoculation of JH−/−, B cell deficient mice, or depletion of T cells by anti-CD4 (GK1.5) antibody, had no impact on CoCr mediated type 2 inflammation. We further demonstrated that the major source of IL33 was macrophages and intra-peritoneal administration of recombinant IL33 rescued the CoCr mediated type 2 response after BTK blockade. These studies indicate that the type 2 immune response caused by solid particles is abrogated by blockade of BTK signaling pathways and that exogenous IL33 is sufficient to rescue this response. These studies elucidate the nature of wear debris-mediated type 2 sterile inflammation and provide potential targets for future therapy.

Dectin-1-Mediated Pathway Contributes to Fusarium proliferatum-Induced CXCL-8 Release from Human Respiratory Epithelial Cells.

Fusarium species are causative agents of human respiratory disorders and are distributed widely in our environment. Little is known of their interaction with human respiratory epithelial cells, which may contribute to allergic airway responses. In this study, we report on the release of C–X–C motif chemokine ligand 8 (CXCL-8) from human bronchial epithelial BEAS-2B cells upon stimulation with Fusarium proliferatum extracts. F. proliferatum-induced cytokine release from BEAS-2B cells was determined by cytokine array and CXCL-8 enzyme-linked immunosorbent assay (ELISA) kits. Blocking antibodies and signaling pathway inhibitors were employed to delineate cell surface receptors and signaling pathways participating in CXCL-8 release. F. proliferatum extracts induced the release of CXCL-8 in a time-dependent manner. The dectin-1 receptor ligands, curdlan and laminarin, reduced CXCL-8 release. Cells pre-treated with anti-Dectin-1 antibodies (2 µg/mL) decreased CXCL-8 release by 24%. Furthermore, F. proliferatum-stimulated CXCL-8 release was reduced by 32%, 53%–81%, 40% and 26% after BEAS-2B cells were pretreated with activation inhibitors of spleen tyrosine kinase (Syk)—piceatannol—, mitogen-activated protein kinases (MAPKs)—PD98059, U0126, SB202190, SP600125—, phosphatidylinositol-3-kinase (PI3K)—LY294002—and nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB)—BAY117082—, respectively. These results suggest that Dectin-1-mediated activation of the Syk, MAPKs, PI3K and NF-κB signaling pathways contributes to F. proliferatum-stimulated CXCL-8 release from BEAS-2B cells and provides an important basis for developing novel therapeutic strategies in clinical allergy.

The Systemic Lupus Erythematosus-Associated Single Nucleotide Polymorphism rs1143678 in Integrin αM Cytoplasmic Tail Generates a 14-3-3ζ Binding Site That Is Proinflammatory.

The leukocyte integrin αMβ2 (CR3 or Mac-1) has both proinflammatory and immune regulatory functions. Genome-wide association studies have identified several ITGAM (αM subunit) single nucleotide polymorphisms that are associated with systemic lupus erythematosus. The single nucleotide polymorphism rs1143678 substitutes Pro1146 for Ser in the integrin αM cytoplasmic tail. A detailed functional characterization of this substitution is lacking. Using transfected human cell lines, reconstituted mouse bone marrow neutrophils, and bone marrow-derived macrophages (BMDMs), we showed that P1146S (PS) substitution promoted integrin αMβ2-mediated adhesion, spreading, and migration of cells on iC3b and fibrinogen. In the presence of LPS together with iC3b or fibrinogen, the expression levels of IL-6 and TNF-α in integrin αM(PS)β2 BMDMs were significantly higher than those of integrin αM(wild-type)β2 BMDMs, and they showed faster kinetics of Erk1/2 activation through the src family kinase(s)-Syk signaling pathway. Integrin αM(PS)β2 BMDMs also exhibited higher levels of active RhoA and phagocytic activity. Mechanistically, P1146S substitution in the αM cytoplasmic tail generates a noncanonical 14-3-3ζ binding site that modulates integrin αM(PS)β2 outside-in signaling.

The pattern recognition receptor, Mincle, is essential for maintaining the M1 macrophage phenotype in acute renal inflammation

Mincle (macrophage-inducible C-type lectin, Clec4e) is a transmembrane pattern recognition receptor involving the innate immunity, but its role in kidney disease is still unexplored. In the obstructed kidney of the unilateral ureteral obstruction model of renal injury, Mincle was specifically detected in the infiltrating M1 macrophages (CD68+iNOS+ cells) on day one but was rapidly reduced following reduction of M1 macrophages during the progression of kidney injury. Interestingly, Mincle-expressing macrophages were progressively increased in the cisplatin-induced acute kidney injury model, where iNOS expression was detected in the CD68+ cells following Mincle induction. Adaptive transfer of Mincle+ M1 macrophages largely promoted cisplatin-induced renal inflammation, which was prevented by the knockdown of Mincle in the transferred cells. Mincle was tightly regulated by TLR4/NF-κB signaling as evidenced by the binding of NF-κB/p65 to the promoter region of Mincle in LPS-primed macrophages. Blocking TLR4 or NF-κB suppressed LPS-induced Mincle expression on macrophages. Importantly, Mincle was found to be essential for maintaining the inflammatory phenotypes of M1 macrophages through the Syk signaling pathway since knockdown of Mincle or inhibition of Syk suppressed LPS-induced IL-1β, MCP-1, and iNOS expression. Thus, Mincle is induced specifically on M1 macrophages, where Mincle-Syk signaling promotes and maintains inflammatory phenotypes of M1 macrophages in acute renal inflammation. Hence, targeting Mincle may be a novel therapy for acute kidney injury associated with M1 macrophages.

Downregulation of the Syk Signaling Pathway in Intestinal Dendritic Cells Is Sufficient To Induce Dendritic Cells That Inhibit Colitis

Helminthic infections modulate host immunity and may protect people in less-developed countries from developing immunological diseases. In a murine colitis model, the helminth Heligmosomoides polygyrus bakeri prevents colitis via induction of regulatory dendritic cells (DCs). The mechanism driving the development of these regulatory DCs is unexplored. There is decreased expression of the intracellular signaling pathway spleen tyrosine kinase (Syk) in intestinal DCs from H. polygyrus bakeri-infected mice. To explore the importance of this observation, it was shown that intestinal DCs from DC-specific Syk(-/-) mice were powerful inhibitors of murine colitis, suggesting that loss of Syk was sufficient to convert these cells into their regulatory phenotype. DCs sense gut flora and damaged epithelium via expression of C-type lectin receptors, many of which signal through the Syk signaling pathway. It was observed that gut DCs express mRNA encoding for C-type lectin (CLEC) 7A, CLEC9A, CLEC12A, and CLEC4N. H. polygyrus bakeri infection downmodulated CLEC mRNA expression in these cells. Focusing on CLEC7A, which encodes for the dectin-1 receptor, flow analysis showed that H. polygyrus bakeri decreases dectin-1 expression on the intestinal DC subsets that drive Th1/Th17 development. DCs become unresponsive to the dectin-1 agonist curdlan and fail to phosphorylate Syk after agonist stimulation. Soluble worm products can block CLEC7A and Syk mRNA expression in gut DCs from uninfected mice after a brief in vitro exposure. Thus, downmodulation of Syk expression and phosphorylation in intestinal DCs could be important mechanisms through which helminths induce regulatory DCs that limit colitis.

Dextran sulfate triggers platelet aggregation via direct activation of PEAR1

Dextran sulfate (DxS; Mr 500 kD) induces fibrinogen receptor (αIIbβ3) activation via CLEC-2/Syk signaling and via a Syk-independent SFK/PI3K/Akt-dependent tyrosine kinase pathway in human and murine platelets. The platelet surface receptor, responsible for the DxS-induced Syk-independent Akt-activation, has hitherto not been identified. We found that DxS elicited a concentration-dependent aggregation of human platelets resulting from direct PEAR1 activation by DxS. Blocking the PEAR1 receptor, in combination with a selective Syk-inhibitor, completely abrogated the DxS-driven platelet aggregation. The DxS-induced Syk-phosphorylation was not affected in Pear1−/− platelets, but Akt-phosphorylation was largely abolished. As a result, the aggregation of Pear1−/− platelets was reduced and reversible, i.e. aggregates were less stable compared to wild-type platelet aggregates. Moreover, DxS-induced Pear1−/− platelet aggregation was fully abrogated by Syk inhibition, indicating that the remaining platelet aggregation of Pear1−/− platelets was Syk dependent. Hence, the Pear1/c-Src/PI3K/Akt- and CLEC-2/Syk-signaling pathways are independently and additively activated during platelet aggregation by DxS. Conclusion. The DxS-induced aggregation of human and murine platelets is the result of activation of PI3K/Akt through direct PEAR1 phosphorylation and parallel Syk-signaling through CLEC-2.

Blockade of either SYK or BTK signaling pathways inhibits microparticle-induced type 2 inflammatory response (IRM11P.628)

Abstract Wear debris microparticle release associated with total joint arthroplasty may contribute to harmful inflammation, osteolysis and implant failure. We examined the role of different molecular signaling pathways in microparticle-mediated inflammation. Intraperitoneal inoculation of cobalt chrome (CoCr) in mice induced a robust innate type 2 response with increases in Th2 cytokines, M2 macrophages, eosinophils and neutrophils compared to controls given vehicle only. Furthermore, this type 2 innate particle-induced response was independent of MYD88/TRIF and partially dependent on Caspase-1 signaling pathways. Blockade of the PGE-2 signaling pathway by administration of Aspirin or Celecoxib prior to CoCr inoculation caused a significant reduction in both neutrophils and macrophages with no effect on eosinophils and Th2 cytokines compared to the mice treated with CoCr + vehicle. Blockade of the SYK signaling pathway with the inhibitor BAY61-3606 or the BTK signaling pathway with Ibrutinib completely abrogated the CoCr-mediated innate inflammation and Th2 cytokines. These studies indicate that the type 2 immune response caused by solid particles is partially modulated by Caspase-1 and PGE-2 pathways and largely abrogated by blockade of upstream SYK and BTK signaling pathways. These studies provide potential targets for controlling the wear debris-mediated inflammation in synovial tissues that can contribute to aseptic loosening and implant failure.

Inhibition of osteoclast activation by phloretin through disturbing αvβ3 integrin-c-Src pathway.

This study was to explore the sequential signaling of disorganization of the actin cytoskeletal architecture by phloretin. RAW 264.7 macrophages were incubated with 1–20 μM phloretin for 5 days in the presence of RANKL. C57BL/6 mice were ovariectomized (OVX) and orally treated with 10 mg/kg phloretin once a day for 8 weeks. Phloretin allayed RANKL stimulated formation of actin podosomes with the concomitant retardation of the vinculin activation. Oral administration of phloretin suppressed the induction of femoral gelsolin and vinculin in OVX mice. The RANK-RANKL interaction resulted in the αvβ3 integrin induction, which was demoted by phloretin. The RANKL induction of actin rings and vacuolar-type H+-ATPase entailed Pyk2 phosphorylation and c-Src and c-Cbl induction, all of which were blunted by phloretin. Similar inhibition was also observed in phloretin-exposed OVX mouse femoral bone tissues with decreased trabecular collagen formation. Phloretin suppressed the paxillin induction in RANKL-activated osteoclasts and in OVX epiphyseal bone tissues. Also, phloretin attenuated the Syk phosphorylation and phospholipase Cγ induction by RANKL in osteoclasts. These results suggest that phloretin was an inhibitor of actin podosomes and sealing zone, disrupting αvβ3 integrin-c-Src-Pyk2/Syk signaling pathway for the regulation of actin cytoskeletal organization in osteoclasts.

Cobalt-chrome micro-particles induce a robust MyD88-independent type 2 immune response (IRM7P.495)

Abstract Orthopaedic wear debris may contribute to harmful inflammation and implant failure. In this study, we examined whether Cobalt Chrome (CoCr) can trigger inflammatory responses under aseptic conditions. Intra-peritoneal injection of mice with CoCr microparticles induced a type 2 innate immune response with marked increases in M2 macrophages, neutrophils and eosinophils in WT and MYD88/TRIF-/- mice. In contrast, although Th2 cytokine MRNA elevations were intact, a marked decrease in neutrophil and M2 macrophages occurred in Caspase-1-/- mice compared to wild type mice. SYK pathway blockade with the inhibitor BAY 61-3606 caused a marked general decrease in type 2 inflammation. Adjuvant properties of CoCr particles were assessed by immunizing mice with CoCr+OVA peptide after transfer of CFSE-labeled OVA specific DO11.10 CD4+ T cells. After 7 days, marked increases in OVA-specific T cell proliferation and IL-4 production were observed compared to mice immunized with OVA alone. To more closely approximate effects of wear debris in joint replacements, localized immune cell infiltrates were examined after intra-articular knee injections of CoCr particles. Infiltration of specific immune cells and mRNA expression were similar to peritoneal inoculation. These studies indicate that the type 2 immune response is triggered by solid particles, independent of toll like receptor signalling, and differentially modulated by Inflammasome and SYK signaling pathways

Alternaria-Induced Releases Of IL-1 Alpha and IL-1 Beta From Airway Epithelial Cells Through Syk and PKC Signaling Pathways

Alternaria-Induced Releases Of IL-1 Alpha and IL-1 Beta From Airway Epithelial Cells Through Syk and PKC Signaling Pathways

Lipid Raft Is Required for PSGL-1 Ligation Induced HL-60 Cell Adhesion on ICAM-1

P-selectin glycoprotein ligand-1 (PSGL-1) and integrins are adhesion molecules that play critical roles in host defense and innate immunity. PSGL-1 mediates leukocyte rolling and primes leukocytes for integrin-mediated adhesion. However, the mechanism that PSGL-1 as a rolling receptor in regulating integrin activation has not been well characterized. Here, we investigate the function of lipid raft in regulating PSGL-1 induced β2 integrin-mediated HL-60 cells adhesion. PSGL-1 ligation with antibody enhances the β2 integrin activation and β2 integrin-dependent adhesion to ICAM-1. Importantly, with the treatment of methyl-β-cyclodextrin (MβCD), we confirm the role of lipid raft in regulating the activation of β2 integrin. Furthermore, we find that the protein level of PSGL-1 decreased in raft fractions in MβCD treated cells. PSGL-1 ligation induces the recruitment of spleen tyrosine kinase (Syk), a tyrosine kinase and Vav1 (the pivotal downstream effector of Syk signaling pathway involved in cytoskeleton regulation) to lipid raft. Inhibition of Syk activity with pharmacologic inhibitor strongly reduces HL-60 cells adhesion, implicating Syk is crucial for PSGL-1 mediated β2 integrin activation. Taken together, we report that ligation of PSGL-1 on HL-60 cells activates β2 integrin, for which lipid raft integrity and Syk activation are responsible. These findings have shed new light on the mechanisms that connect leukocyte initial rolling with subsequent adhesion.

Dual SYK/JAK Inhibition Has a Broader Anti-Tumor Activity In Both ABC and GCB Types Of Diffuse Large B Cell Lymphoma

With increasing understanding of the genetic basis of diffuse large B cell lymphoma (DLBCL), more targeted therapies have been developed. However, most of these therapies have activities only against a subset of DLBCL, activated B-cell like subtype (ABC), in particular, where the BCR pathway is known to be chronically active. Specific single-molecule directed therapies, although effective, often induce resistance over long term treatment. Agents with broader activities are needed for the treatment of this heterogeneous disease. Since both the BCR and JAK/STAT pathways are strongly implicated in the pathogenesis of DLBCL, in the present study, we evaluated the anti-lymphoma activity of PRT062070 (PRT2070), a novel compound that dually targets both JAK and SYK signaling pathways. We analyzed a panel of DLBCL cells lines, of both ABC and germinal center B-cell like (GCB) subtypes, as well as DLBCL patient samples, for cellular and molecular events affected by PRT2070.Immunoblotting analyses showed that ABC and GCB subtype of DLBCL cells exhibit different JAK/STAT and BCR signaling profiles. For instance, AKT was highly expressed in GCB cells, whereas STAT3 was more strongly expressed in ABC cells. In GCB cell lines, PRT2070 blocked G1/S transition and caused cell cycle arrest. In contrast, in ABC cells, the drug induced apoptosis and down-regulated MCL1 protein. Furthermore, array of PRT2070-treated ABC subtype of DLBCL cells revealed that several STAT3 regulated cytokines and chemokines, including IL10, were down-regulated, confirming that PRT2070 affects ABC-DLBCL cells via JAK/STAT pathway. Genetic knockdown of both JAK and SYK reduced the growth and the survival of DLBCL cells more pronouncedly than knockdown of JAK or SYK alone, suggesting the anti-tumor activity of PRT2070 was mediated by dual inhibition of JAK and SYK signaling pathways. Importantly, JAK/STAT and BCR signaling can be blocked by PRT2070 in GCB and non-GCB primary human DLBCL cells, which led to death of these cells. Our work provided mechanistic insights into the actions of JAK/SYK dual inhibitor PRT2070 suggesting that the drug may be a potent treatment of DLBCL with a broader anti-tumor activity in both ABC and GCB subtypes of the lymphoma. Disclosures:Coffey:Portola Pharmaceuticals: Employment. Pandey:Portola Pharmaceuticals: Employment.

Streptochlorin Suppresses Allergic Dermatitis and Mast Cell Activation via Regulation of Lyn/Fyn and Syk Signaling Pathways in Cellular and Mouse Models

Allergic diseases are chronic inflammatory conditions with specific immune and inflammatory mechanisms. Scientific interest in understanding the mechanisms and discovering novel agents for the prevention and treatment of allergic disease is increasing. Streptochlorin, a small compound derived from marine actinomycete possesses anti-angiogenic and anti-tumor activities. However, the anti-allergic effects and underlying mechanisms remain to be elucidated. In the present study, we investigated the effect of streptochlorin on allergic responses in vitro and in vivo. Streptochlorin inhibited degranulation and production of tumor necrosis factor-α and IL-4 by antigen-stimulated mast cells. Streptochlorin also inhibited the phosphorylation of Akt and the mitogen-activated protein kinases (MAPKs), including p38, ERK, and JNK. Further, streptochlorin reduced the phosphorylation of Syk in RBL-2H3 cells and inhibited the activity of Lyn and Fyn. Furthermore, administration of streptochlorin suppressed the allergic reactions in both passive cutaneous anaphylaxis reaction and 2, 4-dinitrofluorobenzene (DNFB)-induced allergic dermatitis in mice model. Considering the data obtained, we report for the first time that streptochlorin possess anti-allergic properties. The underlying mechanism of streptochlorin in exhibiting potent anti-allergic activity might be through the inhibition of the Lyn/Fyn and Syk signaling pathways.

CCN4 induces vascular cell adhesion molecule-1 expression in human synovial fibroblasts and promotes monocyte adhesion

CCN4 is a cysteine-rich protein that belongs to the Cyr61, CTGF, Nov family of matricellular proteins. Here, we investigated the intracellular signaling pathways involved in CCN4-induced vascular cell adhesion molecule-1 expression in human osteoarthritis synovial fibroblasts. Stimulation of OASFs with CCN4 induced VCAM-1 expression. CCN4-induced VCAM-1 expression was attenuated by αvβ5 or α6β1 integrin antibody, Syk inhibitor, PKCδ inhibitor (rottlerin), JNK inhibitor (SP600125), and AP-1 inhibitors (curcumin and tanshinone). Stimulation of cells with CCN4 increased Syk, PKCδ, and JNK activation. Treatment of OASFs with CCN4 also increased c-Jun phosphorylation, AP-1-luciferase activity, and c-Jun binding to the AP-1 element in the VCAM-1 promoter. Moreover, up-regulation of VCAM-1 increased the adhesion of monocytes to OASF monolayers, and this adhesion was attenuated by transfection with a VCAM-1 siRNA. Our results suggest that CCN4 increases VCAM-1 expression in human OASFs via the Syk, PKCδ, JNK, c-Jun, and AP-1 signaling pathways. The CCN4-induced VCAM-1 expression promoted monocyte adhesion to human OASFs.

The IL‐36 receptor pathway regulates Aspergillus fumigatus‐induced Th1 and Th17 responses

IL-1 drives Th responses, particularly Th17, in host defense. Sharing the same co-receptor, the IL-1 family member IL-36 exhibits properties similar to those of IL-1. In the present study, we investigated the role of IL-36 in Aspergillus fumigatus-induced human Th responses. We observed that different morphological forms of A. fumigatus variably increase steady-state mRNA of IL-36 subfamily members. IL-36α is not significantly induced by any morphological form of Aspergillus. Most strikingly, IL-36γ is significantly induced by live A. fumigatus conidia and heat-killed hyphae, whereas IL-36Ra (IL-36 receptor antagonist) is significantly induced by heat-killed conidia, hyphae, and live conidia. We also observed that IL-36γ expression is dependent on the dectin-1/Syk and TLR4 signaling pathway. In contrast, TLR2 and CR3 inhibit IL-36γ expression. The biological relevance of IL-36 induction by Aspergillus is demonstrated by experiments showing that inhibition of the IL-36 receptor by IL-36Ra reduces Aspergillus-induced IL-17 and IFN-γ. These data describe that IL-36-dependent signals are a novel cytokine pathway that regulates Th responses induced by A. fumigatus, and demonstrate a role for TLR4 and dectin-1 in the induction of IL-36γ.

Abstract 3010: IL-6 enhances migration and ICAM-1 expression of human oral squamous cell carcinoma involves IL-6 receptor signaling pathway

Abstract Oral squamous cell carcinoma(SCC) has a striking tendency to migration and metastasize. Interleukin-6(IL-6) has been implicated in the promotion of many cancers proliferation and migration. Intercellular adhesion molecule-1(ICAM-1), a member of the immunoglobulin supergene family, is an inducible surface glycoprotein that mediates adhesion-dependent cell-to-cell interactions. However, the effects of IL-6 in migration and ICAM-1 expression in human oral cancer cells are largely unknown. We found that IL-6 increased migration and ICAM-1 expression in human oral cancer cells. Using a specific inhibitor and genetic inhibition of IL-6 receptor, we discovered that the IL-6 receptor is involved in migration and ICAM-1 expression of human oral cancer cells. IL-6-mediated migration and ICAM-1 up-regulation were attenuated by inhibitor of Syk, JNK and AP-1. Activation of the Syk, JNK and AP-1 signaling pathway occurred after IL-6 stimulation. IL-6 induced AP-1 activity was inhibited by Syk and JNK inhibitor. Our results indicated that IL-6 enhances the migration of human oral cancer cells by increasing ICAM-1 expression through the IL-6 receptor, Syk, JNK and AP-1 signal transduction pathway. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3010. doi:1538-7445.AM2012-3010

Loss of Tankyrase-Mediated Destruction of 3BP2 Is the Underlying Pathogenic Mechanism of Cherubism

Cherubism is an autosomal-dominant syndrome characterized by inflammatory destructive bony lesions resulting in symmetrical deformities of the facial bones. Cherubism is caused by mutations in Sh3bp2, the gene that encodes the adaptor protein 3BP2. Most identified mutations in 3BP2 lie within the peptide sequence RSPPDG. A mouse model of cherubism develops hyperactive bone-remodeling osteoclasts and systemic inflammation characterized by expansion of the myelomonocytic lineage. The mechanism by which cherubism mutations alter 3BP2 function has remained obscure. Here we show that Tankyrase, a member of the poly(ADP-ribose)polymerase (PARP) family, regulates 3BP2 stability through ADP-ribosylation and subsequent ubiquitylation by the E3-ubiquitin ligase RNF146 in osteoclasts. Cherubism mutations uncouple 3BP2 from Tankyrase-mediated protein destruction, which results in its stabilization and subsequent hyperactivation of the SRC, SYK, and VAV signaling pathways.