PDE4DIP/Myomegalin as a Golgi–Centrosome Scaffold in Compartmentalized Signaling, Microtubule Organization, and Disease‐Associated Pathway Remodeling

ABSTRACT

PDE4DIP/Myomegalin was originally identified as a Golgi‐ and centrosome‐associated protein that interacts with phosphodiesterase 4D, but subsequent work has placed it within a broader network of organelle‐associated signaling and cytoskeletal regulation. This review examines PDE4DIP/Myomegalin as a coiled‐coil‐rich scaffold linking compartmentalized cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) signaling, Golgi–centrosome organization, microtubule architecture, and disease‐associated pathway remodeling. At the centrosome, long PDE4D‐binding myomegalin forms retain PDE4D3 and restrict local PKA activity, thereby influencing Hedgehog signaling. At the Golgi, AKAP9/AKAP450 provides a major scaffold, while selected myomegalin forms support Golgi‐derived microtubule organization and endoplasmic reticulum–Golgi trafficking. In KRAS‐mutant colorectal cancer models, PDE4DIP promotes tumor growth and MEK inhibitor resistance through Golgi‐associated NF1/RAS pathway remodeling. In non‐small cell lung cancer, PDE4DIP cooperates with AKAP9 to maintain Golgi localization and stability of PKA regulatory subunit II alpha; PDE4DIP loss activates PKA/cAMP response element‐binding protein signaling and suppresses tumor growth. Cardiovascular studies link myomegalin isoform 4 to sarcomeric PKA signaling, co‐occurring PDE4DIP and DES variants to conduction phenotypes, and PDE4DIP dysregulation to left ventricular noncompaction‐associated cellular changes, although the evidence remains context dependent. Neurological and retinal disease associations remain largely exploratory. Recent work links a PDE4DIP–AKAP9 interaction to cytoskeletal integrity and RAS–ERK/AKT signaling in podocyte injury. Overall, PDE4DIP/Myomegalin is best understood as an organelle‐associated organizer whose effects depend on the experimentally reported form, binding partners, and subcellular address rather than on a single linear pathway.