The Expression Regulation and Biological Function of Autotaxin

Abstract

Autotaxin (ATX) is a secreted glycoprotein and functions as a key enzyme to produce extracellular lysophosphatidic acid (LPA). LPA interacts with at least six G protein-coupled receptors, LPAR1-6, on the cell membrane to activate various signal transduction pathways through distinct G proteins, such as Gi/0, G12/13, Gq/11, and Gs. The ATX-LPA axis plays an important role in physiological and pathological processes, including embryogenesis, obesity, and inflammation. ATX is one of the top 40 most unregulated genes in metastatic cancer, and the ATX-LPA axis is involved in the development of different types of cancers, such as colorectal cancer, ovarian cancer, breast cancer, and glioblastoma. ATX expression is under multifaceted controls at the transcription, post-transcription, and secretion levels. ATX and LPA in the tumor microenvironment not only promote cell proliferation, migration, and survival, but also increase the expression of inflammation-related circuits, which results in poor outcomes for patients with cancer. Currently, ATX is regarded as a potential cancer therapeutic target, and an increasing number of ATX inhibitors have been developed. In this review, we focus on the mechanism of ATX expression regulation and the functions of ATX in cancer development.

Keywords: ATX-LPA axis; Autotaxin (ATX); cancer; lysophosphatidic acid (LPA).

Figure 1

ATX-LPA-LPA receptor signaling axis and LPA delivery on the surface of target cell. LPA is mainly synthesized via the ATX-mediated hydrolysis of lysophosphatidylcholine (LPC) and degraded to monoacylglycerol (MAG) through LPP1/3. ATX protein is composed of two N-terminal somatomedin B (SMB)-like domains, a central phosphodiesterase (PDE) domain, and a C-terminal nuclease (NUC)-like domain. The SMB2 domain enables ATX to bind with cell surface integrin, which achieves a highly efficient delivery of LPA to its receptors. When it binds to LPAR_1-6, LPA induces different downstream signal cascades, including Rho, phospholipase C (PLC), mitogen-activated protein kinase (MAPK), phosphatidylinositide 3-kinase (PI3K), and adenylate cyclase (AC), through different G proteins.

Figure 2

Domain structure of the major ATX isoforms. The five splice variants mainly differ by the presence or absence of sequences encoded by exons 12 and 21. Besides, ATXδ and ATXε have four amino acid deletions in exon 19.

Figure 3

Mechanisms of ATX expression regulation. At the transcriptional level, the expression of ATX is influenced by chromatin modification and different transcriptional factors, like NFAT1, AP-1, SP, STAT3, NFκB et al. Some inflammatory cytokines, such as TNF-α, IL-6, and IFNα/β, can influence ATX expression by inducing different downstream signaling cascades. At the post-transcriptional level, RNA binding proteins (HuR and AUF1), RNA methyltransferase (NSUN2), and microRNA (miR-101-3p) bind to the 3’-UTR of ATX mRNA to influence ATX mRNA stability, nuclear export, and translation. ATX expression can be downregulated by a negative feedback loop by LPA. Moreover, the secretion of ATX is also a regulated process.