Abstract
Simple SummaryThe members of the lysyl oxidase (LOX) family initiate covalent cross-linking of the extracellular matrix and contribute to cancer progression. The aim of this study was to build and analyze the first draft of the interaction network of the five members of the LOX family and to determine if it was rewired in cancer. We identified 14 new partners of LOXL2, including α5β1 integrin, and built an interactome of the LOX family comprising 320 proteins, 5 glycosaminoglycans, and 399 interactions. Computational analyses showed that this network participates in extracellular matrix organization and degradation, in cell-matrix interactions, in protein folding and in chaperone activity, and that it is rewired in colorectal carcinoma, with a switch from extracellular matrix organization to protein folding and chaperone activity. This study provides new insights into the molecular mechanisms underlying LOX family involvement in cancer.The members of the lysyl oxidase (LOX) family are amine oxidases, which initiate the covalent cross-linking of the extracellular matrix (ECM), regulate ECM stiffness, and contribute to cancer progression. The aim of this study was to build the first draft of the interactome of the five members of the LOX family in order to determine its molecular functions, the biological and signaling pathways mediating these functions, the biological processes it is involved in, and if and how it is rewired in cancer. In vitro binding assays, based on surface plasmon resonance and bio-layer interferometry, combined with queries of interaction databases and interaction datasets, were used to retrieve interaction data. The interactome was then analyzed using computational tools. We identified 31 new interactions and 14 new partners of LOXL2, including the α5β1 integrin, and built an interactome comprising 320 proteins, 5 glycosaminoglycans, and 399 interactions. This network participates in ECM organization, degradation and cross-linking, cell-ECM interactions mediated by non-integrin and integrin receptors, protein folding and chaperone activity, organ and blood vessel development, cellular response to stress, and signal transduction. We showed that this network is rewired in colorectal carcinoma, leading to a switch from ECM organization to protein folding and chaperone activity.
Highlights
Lysyl oxidase (LOX) was discovered in 1968 by Pinnell and Martin [1], and its canonical role is to catalyze the first step of the covalent cross-linking of two major extracellular matrix (ECM) proteins, collagens and elastin [2]
Comprised of 44 different biomolecules to identify new extracellular and membrane partners of LOXL2, which plays a prominent role in cancer, and of its N-terminal scavenger receptor cysteine-rich domains (SRCR)
Additional, classical, Surface Plasmon Resonance (SPR) assays were performed to investigate the possible binding of LOXL2 to the ectodomain of collagen XIII, laminin-111, perlecan, and α5β1 integrin
Summary
Lysyl oxidase (LOX) was discovered in 1968 by Pinnell and Martin [1], and its canonical role is to catalyze the first step of the covalent cross-linking of two major extracellular matrix (ECM) proteins, collagens and elastin [2]. The LOX family plays additional, non-canonical, roles in organ development [11] and cancer [12,13], as shown for LOX [14], LOXL1 [3], LOXL2 [4], LOXL3 [5], and LOXL4 [15,16], and reviewed in [17,18,19,20,21,22,23,24,25] Beside their activity as amine oxidases, LOXL2 regulates extracellular and intracellular cell signaling pathways [4], LOXL3 is able to deacetylate and deacetyliminate STAT3 to control inflammatory response [26], and LOX and LOXL2 regulate transcription [27]. The enzymes of the LOX family exert their biological functions both in the extracellular matrix and within the cells
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