TIMPs as multifacial proteins

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Abstract

Tissue inhibitors of metalloproteinases (TIMPs) are natural inhibitors of matrix metalloproteinases (MMPs) found in most tissues and body fluids. By inhibiting MMPs activities, they participate in tissue remodeling of the extracellular matrix (ECM). The balance between MMPs and TIMPs activities is involved in both normal and pathological events such as wound healing, tissue remodeling, angiogenesis, invasion, tumorigenesis and metastasis. The intracellular signalling controlling both TIMPs and MMPs expression begins to be elucidated and gaining insights into the molecular mechanisms regulated by TIMPs and MMPs could represent a new approach in the development of potential therapeutics. Numerous investigations have pointed out that TIMPs exhibit multifunctional activities distinct from MMP inhibition. In this review, we detailed the multiple activities of TIMPs in vivo and in vitro and we reported their implication in physiological and pathological processes. Further, we documented recent studies of their role in hematopoiesis and we itemized the different signalling pathways they induced.

Introduction

The extracellular matrix (ECM) is a dynamic network of interacting macromolecules such as collagens, fibronectin, laminin and proteoglycans. These components modulate cellular behavior by creating influential cellular environments. The turnover of extracellular matrix is an integral part of normal and pathological processes such as development, tissue remodeling, cell growth and differentiation, invasion and metastasis [1], [2]. ECM components are digested by different proteinases among them, the matrix metalloproteinases (MMPs). MMPs represent a family of zinc dependent endopeptidases, including collagenases, gelatinases and stromelysins [3]. To avoid excessive proteolysis and tissue damage, the proteolytic activities are highly regulated in a precise and coordinated manner through different processes such as: (1) regulation of proteinases transcription and translation by growth factors or cytokines, cell–ECM or cell–cell contacts, and oncogene expression; (2) proteolytic activity inhibition by their natural inhibitors, the Tissue Inhibitors of Metalloproteinases (TIMPs). Besides their MMP inhibitory activity, TIMPs exhibit other various biological activities that are documented in this review.

Section snippets

General aspects

Four TIMPs have been currently characterized in human and designated as TIMP-1, -2, -3 and -4. They are expressed by a variety of cell types and present in most tissues and body fluids. TIMPs are natural MMPs inhibitors and inhibit the MMPs proteolytic activity by forming noncovalent 1:1 stoechiometric complexes that are resistant to heat denaturation and proteolytic degradation [4]. Although they all inhibit MMPs proteolytic activity, TIMPs differ in many aspects including solubility,

TIMPs as multifunctional proteins

The primary action described for TIMPs was their ability to inhibit matrix metalloproteinases but numerous studies have reported a wide variety of other functions (Table 2). A part of them are attributed to MMP inhibition but TIMPs also exhibit cellular activities that seem to be independent of MMP inhibition.

TIMPs in cancer

Metastasis development is a complex series of events involving angiogenesis and ECM degradation essential for the spreading and proliferation of cancer cells. These events involve MMPs as well as TIMPs activities. An unbalance between these activities results in an excessive ECM degradation involved in tumor invasion and metastasis [74], [75], [76]. Expression of both MMPs and TIMPs have been compared in normal and tumoral tissues [77], [78]. Although differences in the expression of these

TIMPs in hematopoiesis

The development of hematopoiesis from stem cells has been extensively studied and many cytokines and growth factors have been found to control hematopoiesis [99]. The extracellular matrix of the hematopoietic microenvironment plays also a crucial role in both differentiation and proliferation of the erythroid lineage [100]. Indeed, in the hematopoietic microenvironment, stroma cells, including macrophages, fibroblasts, adipocytes and endothelial cells, support maintenance of hematopoietic cells

Intracellular signalling induced by TIMPs

The cell growth-promoting function of TIMPs was suggested to be a direct cellular effect that could be mediated by a putative receptor. Previous findings reported the presence of TIMP-1 binding sites on human keratinocytes and K562 erythroleukemia cells [32], [106]. The presence of both high (Kd=0.15 nM) and low (Kd=35 nM) affinity binding sites for TIMP-2 has been evidenced in Raji cells [40]. Nevertheless, the apparent molecular weight of the putative TIMP-1 or TIMP-2 receptor seems depend on

Conclusion

In this review we have illustrated the multiple faces of TIMPs that appear as multifunctional proteins involved in several physio-pathological events and we report recent advances on the TIMPs multifunctional properties which complete reviews already published [115], [116], [117], [118], [119]. Recent years have evidenced major advances in the knowledge of these various biological activities, and based on this, TIMPs could appear as a new type of inhibitors in cancer therapy. Nevertheless

Emmanuelle Petitfrère (41 years old) obtained his Ph.D. in Biochemistry in 1991 at the University of Reims, France. She first initiated her work in the Laboratory of Hematology (University Hospital Robert Debré, Reims) prior to integrate the Laboratory of Biochemistry where she is currently (CNRS FRE 2534 “Matrice Extracellulaire et Régulations Cellulaires”)—HDR 2001 (Habilitation à Diriger des Recherches).

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    Emmanuelle Petitfrère (41 years old) obtained his Ph.D. in Biochemistry in 1991 at the University of Reims, France. She first initiated her work in the Laboratory of Hematology (University Hospital Robert Debré, Reims) prior to integrate the Laboratory of Biochemistry where she is currently (CNRS FRE 2534 “Matrice Extracellulaire et Régulations Cellulaires”)—HDR 2001 (Habilitation à Diriger des Recherches).

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