CCN3 as a moonlighting signaling protein: a potential model for dual nuclear and extracellular functions across the CCN family.

Originally identified in the 1990s as an extracellular matrix (ECM) protein, Cellular Communication Network factor 3 (CCN3) was recognized as a member of a structurally related family of six proteins sharing a conserved tetramodular organization and broad regulatory functions in biological processes such as cell proliferation, attachment, migration, differentiation, wound healing, and angiogenesis, as well as in pathological conditions including fibrosis and tumorigenesis. Among these proteins, CCN3 rapidly emerged as the first tumor-suppressive member capable of negatively regulating cell growth in both normal and pathological contexts. A conceptual shift emerged following observations that, in addition to full-length CCN3 detected in the extracellular matrix, amino-truncated CCN3 proteoforms are targeted to the nucleus. In addition to physically interacting with the Rpb7 subunit of RNA polymerase II (Pol II), CCN3 binds to the promoter region of PAI-2 and exhibits transcriptional regulatory activity both in vitro and ex vivo. The dual localization and functional versatility of CCN3 led to the proposal that this protein may function as a "moonlighting" factor capable of integrating extracellular cues with nuclear transcriptional regulation. This conceptual framework, however, has remained relatively underexplored. The nuclear localization of other family members, together with the more recent observation that nuclear CCN6 physically interacts with RNA polymerase II, may extend this concept to the entire CCN protein family. By revisiting and integrating a substantial body of published data that has remained insufficiently acknowledged, this review aims to underscore the biological significance of CCN proteoforms in the nuclei of tumor cells. The demonstration of physical interactions between CCN3 and components of the central transcriptional machinery invites reconsideration of the prevailing ECM-centered view of CCN proteins and opens new perspectives on their biological roles.