Autotaxin Implication in Cancer Metastasis and Autoimunne Disorders: Functional Implication of Binding Autotaxin to the Cell Surface

cancers Review Autotaxin Implication in Cancer Metastasis and Autoimunne Disorders: Functional Implication of Binding Autotaxin to the Cell Surface Olivier Peyruchaud 1, * , Lou Saier 1 and Raphaël Leblanc 2 1 2 * INSERM, Unit 1033, Université Claude Bernard Lyon 1, 69372 Lyon, France; Centre de Recherche en Cancérologie de Marseille, Institut Poli-Calmettes, INSERM, Unit 1068, University Aix/Marseille, 13009 Marseille, France; Correspondence: ; Tel.: +3-34-78-77-86-72 Received: 29 November 2019; Accepted: 29 December 2019; Published: 31 December 2019



 Abstract: Autotaxin (ATX) is an exoenzyme which, due to its unique lysophospholipase D activity, is responsible for the synthesis of lysophosphatidic acid (LPA). ATX activity is responsible for the concentration of LPA in the blood. ATX expression is increased in various types of cancers, including breast cancer, where it promotes metastasis. The expression of ATX is also remarkably increased under inflammatory conditions, particularly in the osteoarticular compartment, where it controls bone erosion. Biological actions of ATX are mediated by LPA. However, the phosphate head group of LPA is highly sensitive to degradation by the action of lipid phosphate phosphatases, resulting in LPA inactivation. This suggests that for efficient action, LPA requires protection, which is potentially achieved through docking to a carrier protein. Interestingly, recent reports suggest that ATX might act as a docking molecule for LPA and also support the concept that binding of ATX to the cell surface through its interaction with adhesive molecules (integrins, heparan sulfate proteoglycans) could facilitate a rapid route of delivering active LPA to its cell surface receptors. This new mechanism offers a new vision of how ATX/LPA works in cancer metastasis and inflammatory bone diseases, paving the way for new therapeutic developments. Keywords: autotaxin; lysophosphatidic acid; integrins; heparan sulfate; platelets; metastasis; inflammation; osteoclast; T cells 1. Introduction The name autotaxin (ATX), proposed by Stracke and colleagues in 1992, arose during the characterization of a new potent autocrine motility-stimulating protein produced by human A2058 melanoma cells [1]. Stracke’s lab also demonstrated that ATX augments the invasive and metastatic potential of Rat Sarcoma (RAS)-transformed cells [2] before the characterization that ATX and lysophospholipase D (lysoPLD) actually correspond to the same protein [3,4]. ATX lysoPLD activity leads to the production of lysophosphatidic acid (LPA) through the degradation of a series of lysophospholipid precursors, of which lysophosphatidylcholine (LPC) is the most abundant in blood [5] (Figure 1). ATX is a multidomain protein with a somatomedin-B (SMB1,2)-like domain, a central phosphodiesterase catalytic domain (PDE), and a C-terminal inactive catalytic nuclease domain (NUC) (Figure 1). LPA exhibits growth factor-like activity due to the activation of a series of six different G protein-coupled receptors (Table 1). Expression of ENPP2, the ATX gene, is regulated by cytokines, growth factors and hormones (Table 2). Cancers 2020, 12, 105; doi:10.3390/cancers12010105 www.mdpi.com/journal/cancers Cancers 2020, 12, 105 2 of 15 Cancers 2020, 12, x FOR PEER REVIEW 2 of 14 Blood circulation SMB2 SMB1 H2N Cells: Oligodendrocytes Cancer cells Inflammation: Adipocytes Chondrocytes Broncoalveolar fluid (IPF) Synovial fluid (RA) Osteoclasts… Catalytic domain (PDE) Lasso Nuclease domain (NUC) COOH T210 CH2CH2N+(CH3)3 O O P OO CCC O OH OC Lysophosphatidylcholine LPC OO P OO CCC O OH O C + Lysophosphatidic acid LPA CH2CH2N+(CH3)3 Choline Figure 1. Origin, structure and enzymatic activity of autotaxin (ATX). T210 identifies the amino acid Figure 1. Origin, structure and enzymatic activity of autotaxin (ATX). T210 identifies the amino acid required for ATX lysophospholipase D (lysoPLD) activity. IPF, idiopathic pulmonary fibrosis; RA, required for ATX lysophospholipase D (lysoPLD) activity. IPF, idiopathic pulmonary fibrosis; RA, rheumatoid arthritis. rheumatoid arthritis. Table 1. Characteristics of lysophosphatidic acid (LPA) receptors. Table 1. Characteristics of lysophosphatidic acid (LPA) receptors Receptors Receptors G Proteins Cellular Responses G Proteins Cellular Responses Neurite retraction [6,7], AC inhibition [8], SRE activation [6], 2+ ]i, Neurite retraction [6,7],[Ca AC inhibition [8], SRE activation [6],[8], increased increased IP production, MAPK activation stress Gi/o , Gq/11 , G12,132+ LPA1 /Edg2 fiber formation, incorporation [6],fiber inhibition of Gi/o, Gq/11, [Ca ]i, IP production, MAPKBrdU activation [8], stress formation, LPA1/Edg2 arachidonic acid release [8]. G12,13 BrdU incorporation apoptosis, [6], inhibition of apoptosis, arachidonic acid Neurite retraction [8], AC inhibition [9], SRE activation, release [8]. 2+ ]i [9], IP production [8], MAPK activation [8], increased[8], [CaAC retraction inhibition [9], SRE activation, increased Gi/o , Gq/11 , GNeurite LPA2 /Edg4 12,13 stress fiber formation, BrdU incorporation [6], inhibition of Gi/o, Gq/11, [Ca2+]i [9], IP production [8], MAPK activation [8], stress fiber apoptosis, arachidonic acid release [8]. LPA2/Edg4 G12,13 formation, BrdU incorporation [6], inhibition of apoptosis, arachidonic AC inhibition [8], increased [Ca2+ ]i, IP production, MAPK Gi/o , Gq/11 LPA3 /Edg7 acid release [8]. activation, arachidonic acid release [8]. AC inhibition [8], increased [Ca2+]i, IP production, MAPK activation, LPA3/Edg7 Gi/o, Gq/11 AC stimulation, increased [Ca2+ ]i [10], zif268 activation, arachidonic acid release [8]. Gq/11 , G12/13 , Gs , (Gi ) LPA4 /p2y9/GPR23 neurite retraction, cell aggregation [10], stress fiber formation Gq/11, G12/13, AC stimulation, increased [Ca2+]i [10], [11].zif268 activation, neurite LPA4/p2y9/GPR23 Gs, (Gi) retraction, cell aggregation [10], stress fiber formation neurite [11]. AC stimulation, increased [Ca2+ ]i, IP production, Gq/11 , G12/13 LPA /GPR92/GPR93 5 2+ LPA5/GPR92/GPR93 Gq/11, G12/13 AC stimulation, increased [Ca ]i, IP production, retraction [7]. neurite retraction [7]. G 12/13, G (G s), , (G ), (G ) LPA /p2y5 CRE activation, neurite retraction, membrane shedding [10]. 6 s 12/13 iCRE activation, neurite retraction, membrane LPA6/p2y5 shedding [10]. (Gi) AC, adenylate cyclase; BrdU, bromodeoxyuridine; CRE, cAMP response element; IP, inositol phosphate; MAPK, AC, adenylate protein cyclase;kinase; BrdU, bromodeoxyuridine; CRE, response element; IP, inositol mitogen-activated SRE, serum response element; [Ca2+cAMP ], intracellular calcium concentration. phosphate; MAPK, mitogen-activated protein kinase; SRE, serum response element ; [Ca2+], intracellular calcium concentration. Cancers 2020, 12, 105 3 of 15 Table 2. Regulation of ENPP2 expression. External Signals Transcription Factors Effects Cell Types References EGF nd Upregulation Thy (...truncated)