Insider trading: Extracellular matrix proteins and their non‐canonical intracellular roles

Abstract

General rightsThis document is made available in accordance with publisher policies. Please cite only the published version using the reference above. Full terms of use are available: http://www.bristol.ac.uk/pure/about/ebr-terms Graphical AbstractIt is a given that ECM proteins function outside cells. We evaluate emerging data that implicate noncanonical roles in the cytoplasm or nucleus. We discuss the conceptual and experimental challenges that will need to be met to investigate this under-studied area of ECM biology more rigorously. SummaryIn metazoans, the extracellular matrix (ECM) provides a dynamic, heterogeneous microenvironment that has important supportive and instructive roles. Although the primary site of action of ECM proteins is extracellular, evidence is emerging for noncanonical intracellular roles. Examples include osteopontin, thrombospondins, IGF-binding protein 3 and biglycan, and relate to roles in transcription, cell-stress responses, autophagy and cancer. These findings pose conceptual problems on how proteins signalled for secretion can be routed to the cytosol or nucleus, or can function in environments with diverse redox, pH and ionic conditions. We review evidence for intracellular locations and functions of ECM proteins, and current knowledge of the mechanisms by which they may enter intracellular compartments. We evaluate the experimental methods that are appropriate to obtain rigorous evidence for intracellular localisation and function. Better insight into this under-researched topic is needed to decipher the complete spectrum of physiological and pathological roles of ECM proteins.

The significance of TRIP11 and T3 signaling pathway in renal cancer progression and survival of patients.

“…It was also suggested that TRIP11 may play a specific role in secretion of extracellular matrix proteins [34]. Remarkably, disturbances in expression and secretion of ECM proteins contribute to the progression of renal and other cancers [17,35,36]. Thus, disturbed expression of TRIP11 might also contribute to alterations in ECM of renal tumours.…”

A Rapid, Scalable Method for the Isolation, Functional Study, and Analysis of Cell-derived Extracellular Matrix

“…Firstly, the presence of cells and their abundant intracellular proteins can make it difficult to isolate the ECM as a discrete extracellular structure. Indeed, some ECM proteins have roles inside the cell as well as in the ECM 4 ; therefore, the efficient removal of intracellular proteins from cell-derived ECM is vital if the study of proteins within the ECM is not to be confused with their roles inside the cell. Secondly, cell-derived ECM is composed of many large, oligomeric proteins, which are often covalently cross-linked upon ECM assembly and are therefore insoluble in standard detergents.…”

Experimental Dissection of Metalloproteinase Inhibition-Mediated and Toxic Effects of Phenanthroline on Zebrafish Development.

“…Best known for their roles in the hydrolysis of otherwise proteolytically resistant ECM proteins, especially during normal and pathological tissue remodeling, these proteases have more recently become recognized as essential components of signal transduction pathways -mediating the presentation of extracellular ligands, availability of cell surface receptors, etc. -and even intracellular processes [3,[6][7][8][9][10].…”