GIPC2 regulation of the PKM2/SREBP1 signaling axis controls adipogenic differentiation of mesenchymal stem cells

Mesenchymal stem cell (MSC) differentiation is a cornerstone of regenerative medicine with a wide range of applications in tissue engineering and translational therapies. However, the molecular mechanisms underlying MSC differentiation remain incompletely understood, preventing the full leveraging of their therapeutic potential. Central to these complex molecular networks are dynamic protein-protein interactions, with scaffolding proteins serving as master coordinators. GAIP-interacting protein C-terminus 2 (GIPC2) functions as an adaptor protein involved in mediating such interactions and may influence MSC fate by regulating differentiation-related signaling pathways. In this study, we identified GIPC2 as a novel regulator of adipogenic differentiation in human umbilical cord-derived MSCs (UC-MSCs). Mechanistically, GIPC2 interacts directly with Pyruvate Kinase M2 (PKM2) via its PDZ domain, promoting PKM2 nuclear translocation. In the nucleus, PKM2 facilitates the activation of sterol regulatory element-binding protein 1 (SREBP1), a transcription factor essential for lipid biosynthesis and adipocyte maturation. Our findings show that GIPC2 drives MSC adipogenic differentiation by orchestrating the PKM2-SREBP1 signaling axis. This study reveals a previously unrecognized regulatory mechanism, highlighting the pivotal role of GIPC2 at the intersection of metabolic regulation and transcriptional control. These insights not only deepen our understanding of MSC differentiation but also open new avenues for enhancing MSC-based therapeutic strategies.