Nuevas interacciones y modificaciones del comportamiento celular mediadas por ADAMTSs y TMPRSS9

En esta Tesis Doctoral hemos abordado el estudio de nuevas modificaciones en el microentorno celular mediadas por metaloproteasas de la familia ADAMTS y la serín-proteasa TMPRSS-9 o poliserasa-1 que afectan al comportamiento celular. Hemos identificado que ADAMTS-12 interacciona con fibulina-2. Ambas, ADAMTS-12 y fibulina-2 han sido asociadas a procesos pro- y anti-tumorales. Sin embargo, su interacción potencia los efectos antitumorales en distintos modelos celulares de cáncer de mama. Además, hemos comprobado que fibulina-2 es sustrato de ADAMTS-4 y ADAMTS-5, las cuales son capaces de procesar la fibulina-2 alterando el microambiente celular y promoviendo efectos pro-tumorales. Sin embargo, la presencia de ADAMTS-12 impide la degradación de fibulina-2 lo que acentúa su papel protector en procesos tumorales. Además, se ha identificado el neurocano como un nuevo sustrato para ADAMTS-12. Los resultados obtenidos indican que esta degradación interviene en la modulación de propiedades como la migración y la adhesión de células del sistema nervioso central, lo cual resulta clave en procesos de reparación o en el desarrollo de patologías relacionadas con alteraciones del comportamiento. En relación a TMPRSS9, en este trabajo se ha llevado a cabo la primera aproximación referente a su potencial participación en procesos tumorales. Esta peculiar proteasa es capaz de potenciar efectos pro-tumorales y cambiar el perfil de adhesión a componentes de la ECM cuando se expresa exógenamente en células de cáncer de páncreas. Estas acciones están mediadas por el procesamiento de pro-uPA

New Insights into ADAMTS Metalloproteases in the Central Nervous System

Components of the extracellular matrix (ECM) are key players in regulating cellular functions throughout the whole organism. In fact, ECM components not only participate in tissue organization but also contribute to processes such as cellular maintenance, proliferation, and migration, as well as to support for various signaling pathways. In the central nervous system (CNS), proteoglycans of the lectican family, such as versican, aggrecan, brevican, and neurocan, are important constituents of the ECM. In recent years, members of this family have been found to be involved in the maintenance of CNS homeostasis and to participate directly in processes such as the organization of perineural nets, the regulation of brain plasticity, CNS development, brain injury repair, axonal guidance, and even the altering of synaptic responses. ADAMTSs are a family of “A disintegrin and metalloproteinase with thrombospondin motifs” proteins that have been found to be involved in a multitude of processes through the degradation of lecticans and other proteoglycans. Recently, alterations in ADAMTS expression and activity have been found to be involved in neuronal disorders such as stroke, neurodegeneration, schizophrenia, and even Alzheimer’s disease, which in turn may suggest their potential use as therapeutic targets. Herein, we summarize the different roles of ADAMTSs in regulating CNS events through interactions and the degradation of ECM components (more specifically, the lectican family of proteoglycans)

Lung Inflammatory Phenotype in Mice Deficient in Fibulin-2 and ADAMTS-12

Interaction between extracellular matrix (ECM) components plays an important role in the regulation of cellular behavior and hence in tissue function. Consequently, characterization of new interactions within ECM opens the possibility of studying not only the functional but also the pathological consequences derived from those interactions. We have previously described the interaction between fibulin2 and ADAMTS-12 in vitro and the effects of that interaction using cellular models of cancer. Now, we generate a mouse deficient in both ECM components and evaluate functional consequences of their absence using different cancer and inflammation murine models. The main findings indicate that mice deficient in both fibulin2 and ADAMTS12 markedly increase the development of lung tumors following intraperitoneal urethane injections. Moreover, inflammatory phenotype is exacerbated in the lung after LPS treatment as can be inferred from the accumulation of active immune cells in lung parenchyma. Overall, our results suggest that protective effects in cancer or inflammation shown by fibulin2 and ADAMTS12 as interactive partners in vitro are also shown in a more realistic in vivo context

Hyalectanase Activities by the ADAMTS Metalloproteases

The hyalectan family is composed of the proteoglycans aggrecan, versican, brevican and neurocan. Hyalectans, also known as lecticans, are components of the extracellular matrix of different tissues and play essential roles in key biological processes including skeletal development, and they are related to the correct maintenance of the vascular and central nervous system. For instance, hyalectans participate in the organization of structures such as perineural nets and in the regulation of neurite outgrowth or brain recovery following a traumatic injury. The ADAMTS (A Disintegrin and Metalloprotease domains, with thrombospondin motifs) family consists of 19 secreted metalloproteases. These enzymes also perform important roles in the structural organization and function of the extracellular matrix through interactions with other matrix components or as a consequence of their catalytic activity. In this regard, some of their preferred substrates are the hyalectans. In fact, ADAMTSs cleave hyalectans not only as a mechanism for clearance or turnover of proteoglycans but also to generate bioactive fragments which display specific functions. In this article we review some of the physiological and pathological effects derived from cleavages of hyalectans mediated by ADAMTSs