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

In 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 non‐canonical 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.