Cysteinyl leukotrienes and their receptors: Bridging inflammation and colorectal cancer

Figure 2 Signaling pathways of LTD₄ and CysLT₁R. Upon stimulation with LTD₄, various downstream signaling pathways become activated. LTD₄ induces cell membrane ruffles through phosphoinositide 3-kinase (PI3K) signaling, which in turn stimulates protein kinase Akt/PKB and the small GTPases Rho and Rac. Akt/PKB can inhibit glycogen synthase kinase-3 β (GSK-3β), which comprises the destruction complex for cytosolic β-catenin together with Axin and adenomatous polyposis coli (APC). Inhibition of the destruction complex leads to the accumulation of β-catenin in the cytosol and translocation to the nucleus. In the nucleus, β-catenin interacts primarily with members of the T-cell factor/lymphoid enhancer factor (TCF/LEF) family of transcription factors to activate target genes, leading to the expression of various proteins, such as cyclin D1, COX-2 and c-Myc, which contribute to diverse cellular processes, including proliferation and migration. LTD₄-CysLT₁R signaling also regulates cell proliferation via mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (Erk) pathways. LTD₄-CysLT₁R in turn activates phospholipase C (PLC), Raf-1 and mitogen-activated protein kinase kinase (MEK-1/2). This activation leads to the translocation of p-Erk from the cytosol to the nucleus and interaction with p90^RSK, which can activate various transcription factors. Conversely, LTD₄-CysLT₁R mediates survival through protein kinase Cα (PKCα) and the transcription factor cAMP response element-binding protein (CREB). β-cat: β-catenin.