G protein–coupled receptors are a mainstay of pharmacology and remain the most targeted molecules in clinical history. Typcially,
soluble ligands reach GPCRs and initiate cascades of protein–protein and enzymic interactions that affect cytoplasmic and
nuclear metabolism. Migration, survival, and proliferation are some of the basic cell functions that are regulated by means
of GPCR signaling. Increasingly, the extracellular matrix has become appreciated for its active role in nuancing these functions
and integrating cell–cell communication essential to tissue physiology. The matricellular protein CYR61/CCN1 has recently
been shown to be expressed in response to canonical GPCR-activated signaling pathways. Furthermore, secreted CYR61/CNN1 interacts
with integrins and other elements of the ECM and thereby adds a novel dynamic to GPCR and ECM signaling. Recognition of CYR61/CCN1
as a regulator of crosstalk between intra- and extracellular signaling pathways also opens up new opportunities for experimental
therapeutics.
