FGL2 Signaling Pathway: A Key Role in Inflammation and Tumors

What is FGL2？

FGL2, standing for Fibrinogen-like protein 2, is a pivotal player within the immune system. This protein exhibits similarity to fibrinogen and boasts considerable importance in immune responses. Encoded by the FGL2 gene, it finds expression across various cell types, contributing to its multifaceted impact on immune processes.

Structure and function of FGL2

Structural Insights into FGL2

FGL2, also identified as FGL2-prothrombin, is a significant 64-70 kD type 2 transmembrane protein comprising 439 amino acids (AA). Notably, it shares a 36% homology with the β and γ fibrinogen chains[1]. The protein's architecture encompasses a 70-kD length, housing 439 amino acids (AA). Its N-terminus features a 2 AA-long cytoplasmic domain and a 21-AA-long transmembrane domain. The remaining 416 AA constitute the extracellular domain, forming the foundation of the FGL2 protein structure[2]. The FGL2 gene comprises two exons; exon I codes for the initial 204 amino acids, while exon II encodes the subsequent 234 amino acids[3]. The multifaceted FGL2 protein exists in two distinct forms - membrane-bound FGL2 (mFGL2) and soluble FGL2 (sFGL2)[4]. mFGL2 assembles through three domains: the membrane, transmembrane, and extramembrane domains, whereas sFGL2 solely retains the extracellular domain, subsequently secreted into plasma[5].

Functional Insights of FGL2

FGL2 possesses the unique capability to cleave prothrombin into thrombin autonomously, obviating the need for factors VII or X[6]. This action sets off a cascade reaction that amplifies its significance[7]. As an immunomodulator, FGL2 emerges as a pivotal player in innate immunity. Mounting evidence highlights FGL2's role as a T regulatory (Treg) effector, actively curbing T cell activity in a FoxP3-dependent manner[8-10]. This commanding regulatory capacity extends to the adaptive immune system as well. By pairing with FcγRIIB, FGL2 curtails dendritic cell (DC) maturation[11], influences B cell function[12], and induces FcγRIIB-mediated CD8+ T cell apoptosis[13]. Expanding its influence, FGL2 is intricately intertwined with tumor development, evident from its overexpression in tumors and interstitial inflammatory cells. Immunohistochemical staining of tumor sections reveals heightened FGL2 expression in CD57+, CD68+, CD8+ T cells, and vascular endothelial cells. Recent studies have shown an association between FGL2 and SARS-CoV-2 infection, but the exact mechanism remains unclear [14].

Unraveling FGL2's Impact in Tumor Progression

FGL2 and Gliomas: A Grading Connection

Emerging research underscores FGL2's presence in human gliomas and its pivotal role in steering the transformation from low-grade gliomas (LGGs) to high-grade gliomas (HGGs). This dynamic hints at FGL2's relationship with glioma grading[16]. Within the context of glioblastoma (GBM), FGL2 triggers immune suppression mechanisms that fuel GBM progression[16]. In a revealing study, Latha et al. eliminated FGL2 in GL261 cells, generating stable lines that were injected into mice. Interestingly, mice injected with these modified cells exhibited no tumor formation, underlining FGL2's indispensable role in GBM's invasive tumor formation. Furthermore, FGL2 emerges as a catalyst for macrophage polarization and Treg cell proliferation within the tumor microenvironment, effectively bolstering immunosuppressive functions. Derived from glioma cells, FGL2 wields its immunosuppressive influence by up-regulating CD39 and PD-1 expression levels while restraining CD103+ DC differentiation. In GBM, in vivo targeting of FGL2 expression showcases potential for enhancing immune function and elevating therapeutic outcomes for glioma patients.

Diverse Tumor Influences of FGL2

In diverse tumor scenarios, FGL2's impact remains significant. In the realm of hepatocellular carcinoma (HCC), studies reveal that FGL2 knockdown hinders HCC cell proliferation by arresting G0/G1 cell cycle progression and influencing angiogenesis[17]. Conversely, in liver tumor microenvironments, FGL2 knockdown triggers the accumulation of myeloid-derived suppressor cells (MDSCs), which drive cancer progression[18]. Notably, FGL2's proangiogenic/protumorigenic activities find their nexus in FGF/ERK signaling. This signaling cascade involves FGL2's interaction with FGFR, leading to autophosphorylation and activation, ultimately transmitting signals via diverse downstream pathways including ERK/MAP kinase.

Beyond HCC, the FGL2 narrative continues in prostate cancer and lung cancer realms. By silencing FGL2, a noticeable decline in FGF-2 levels and prostate cancer occurrence in mice was observed[19]. In lung cancer, stromal-derived FGL2 creates an environment conducive to tumor growth by influencing the tumor-promoting microenvironment rather than directly regulating tumor cells. Knockdown of FGL2 disrupts lung cancer progression, inhibits CXCL12-mediated accumulation of MDSCs in the tumor microenvironment (TME), and weakens the role of cancer-associated fibroblasts (CAFs)[19].

Moreover, colorectal cancer (CRC) and lymphoma also experience FGL2's influence. Studies illustrate FGL2's promotion of CRC proliferation both in vitro and in vivo[20]. Additionally, FGL2's role as a prothrombinase might contribute to tumor hypercoagulability and possibly angiogenesis. In the context of B-cell lymphoma, the prothrombin activity of FGL2 in peripheral blood monocytes has garnered attention. Rabizad et al. demonstrated elevated FGL2 prothrombin activity in active non-Hodgkin's lymphoma (NHL), possibly serving as a prospective marker for lymphoma remission[21].

The Role of FGL2 in Signaling Pathways

FGL2, an immune regulator, participates in various signaling pathways associated with inflammatory diseases and tumors. Recent research has highlighted FGL2's pivotal role in the pathogenesis of experimental and human fulminant and chronic viral hepatitis[21]. Investigations reveal that FGL2 obstructs the NF-κB signaling pathway, thereby mitigating DSS-induced inflammatory bowel disease (IBD)[22]. Protein expression levels related to NF-κB signaling, such as p-IKKα/β, IKKα/β, p-IκBα, IκBα, p-p65, p65, and downstream transduction proteins iNOS, Cox-2, and TNF-α, were assessed through western blotting in DSS-induced IBD. The results demonstrated heightened expression of these proteins in FGL2-knockout mice compared to wild-type mice[23].

Furthermore, studies indicate that the elevation of FGL2 in viral fulminant hepatitis (FH) resulting from MHV-3 infection relies on the involvement of complement component 5 (C5) and its receptor C5R[24]. The C5a/C5aR signaling pathway contributes to MHV-3-induced FGL2 expression by activating ERK1/2 and p38 MAPK kinases. Another study also reveals that MHV-3 induces the expression of macrophage prothrombin FGL-2 via the p38 MAPK pathway[25].

Research underscores that FGL2 transcriptional regulation is modulated by the STAT1-dependent pathway and the Sp1/Sp3-STAT1/PU.1 transcriptional complex. A study demonstrates that TNF-α-induced endothelial cell FGL2 enhances microcirculation dysfunction through NF-κB and P38 MAPK signaling pathways. Additionally, it was confirmed that FGL2 activation of this pathway and the NLRP3 inflammasome exacerbates nonalcoholic steatohepatitis (NASH) and contributes to lipid metabolism disorders[26]. These findings substantiate that FGL2 mediated by NF-κB and MAPK signaling pathways accelerates inflammation development. While IL-1 alone fails to regulate FGL2 expression, synergistic action with TNF-α amplifies FGL2 expression via the NF-κB pathway.

Investigations examined hFGL2 gene transcription response to hepatitis B core (HBc) and hepatitis B virus X protein (HBx) proteins. ERK promotes hBC-induced nuclear C-est-2 DNA binding activity and FGL2 induction, whereas JNK promotes HBX-induced nuclear C-est-2 DNA binding activity and FGL2 induction. Notably, ERK and JNK are integral to the three core components of the MAPK pathway, implicating the MAPK signaling pathway in FGL2 transcription. Recent research further suggests that FGL2 deficiency in a mouse model exacerbates UUO-induced renal fibrosis by upregulating STAT6-dependent M2 macrophage polarization[27].

FGL2 Proteins

Recombinant Human Fibroleukin (FGL2) Protein (His)

Click here for more FGL2

Synonym : FGL2 FGL2_HUMAN fibrinogen like 2 Fibrinogen like protein 2 Fibrinogen-like protein 2 Fibroleukin pT49 T49

References:

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