Regulation of autotaxin expression and secretion by lysophosphatidate and sphingosine 1-phosphate

Abstract

This article is available online at http://www.jlr.org Autotaxin (ATX) is a secreted enzyme, which converts extracellular lysophosphatidylcholine (LPC) into lysophosphatidate (LPA). This is an important reaction in cell signaling because LPA activates at least six G proteincoupled receptors to increase cell division, survival, and migration ( 1, 2 ). ATX serves an essential function in embryonic development because ATX knockout mice die in utero at day 9.5 with defects in vasculogenesis and the development of the neural crest ( 3-6 ). In the postnatal organism, the major function of ATX appears to be in wound healing. ATX is produced in response to infl ammation to mediate wound repair. If the infl ammation is not resolved, then high ATX concentrations persist in association with infl ammatory diseases such as arthritis and infl ammatory bowel disease ( 1,7,8 ). In addition, infl ammatory bowel disease and hepatitis can progress to carcinogenesis in these organs ( 1 ). Signifi cantly, increased ATX activity is associated with the growth of breast tumors ( 9, 10 ) and the ATX gene is among the top 40 most upregulated in metastatic cancer ( 11 ). Blocking LPA production by inhibiting ATX activity with ONO-8430506 decreases the fi rst phase of breast tumor growth and subsequent metastasis by about 60 % in mice ( 9, 12 ). Conversely, increasing the low lipid phosphate phosphatase (LPP)1 activity in cancer cells so as to increase LPA turnover in the tumor and attenuate LPA signaling decreased breast tumor growth and metastasis in mice by about 80% ( 13 ). These studies emphasize the importance of ATX in controlling cell signaling in several physiological and pathological conditions. Consequently, it is important to understand how ATX activity and signaling by LPA are regulated. The present work focuses on the role of ATX and how its expression is controlled.Abstract Autotaxin (ATX) is a secreted enzyme, which produces extracellular lysophosphatidate (LPA) from lysophosphatidylcholine (LPC). LPA activates six G protein-coupled receptors and this is essential for vasculogenesis during embryonic development. ATX is also involved in wound healing and infl ammation, and in tumor growth, metastasis, and chemo-resistance. It is, therefore, important to understand how ATX is regulated. It was proposed that ATX activity is inhibited by its product LPA, or a related lipid called sphingosine 1-phosphate (S1P). We now show that this apparent inhibition is ineffective at the high concentrations of LPC that occur in vivo. Instead, feedback regulation by LPA and S1P is mediated by inhibition of ATX expression resulting from phosphatidylinositol-3-kinase activation. Inhibiting ATX activity in mice with ONO-8430506 severely decreased plasma LPA concentrations and increased ATX mRNA in adipose tissue, which is a major site of ATX production. Consequently, the amount of inhibitor-bound ATX protein in the plasma increased. We, therefore, demonstrate the concept that accumulation of LPA in the circulation decreases ATX production. Howeve...

Autotaxin signaling, purinergic receptors and lung damage

“…How the initial secretion relates to the subsequent protein synthesis is not known, but our data suggest not yet described control mechanisms for ATX expression; previous work indicate an inhibitory feedback loop between LPA and ATX in e.g. thyroid and melanoma cell lines [4] . Further work showed that P2X4 and P2X7 co-localize in response to TDI, and that ATX is rapidly concentrated in plasma membrane vesicles, presumably as a step preceding the secretion of ATX.…”

“…Thus, death resulting from hyperoxic toxicity in mice depends on ATX induction in invariant natural killer cells (iNKT cells), often described as a bridge between innate and adaptive immunity, but also depends on extracellular ATP (that is a ligand for P2X7) [31] . Interestingly, not only hyperoxic injury but also hypoxia induce ATX levels [19] , so cell damage might be the common denominator in these studies [19,31] and, as mentioned above, ATX is implicated in wound healing [4] .…”

“…In further studies these questions will be addressed. The involvement of ATX in wound healing [4] and cell motility [7,19] suggests additional roles for ATX in the bronchial tissue remodeling seen in occupational asthma [20] . So also the remodeling should be studied in this connection.…”

“…embryogenesis and basic cell functions including growth, migration, DNA repair etc. Several studies indicate a role for the ATX-LPA axis in inflammatory conditions of the lung such as asthma [2] and idiopathic lung fibrosis [3] , but also in wound healing [4] , rheumatoid arthritis [5,6] and in linking inflammation and carcinogenesis in e.g. mammary cancer [7] .…”

“…studies describe endogenous regulatory factors of importance for inflammation such as TNF- and IL-1 [4] . ATX binds to integrins and other structures on the cell surface, which may confer strict localization of LPA delivery to LPARs [8] .…”