Myomegalin regulates Hedgehog pathway by controlling PDE4D at the centrosome

Abstract

Mutations in the Hedgehog (Hh) signaling are implicated in birth defects and cancers, including medulloblastoma, one of the most malignant pediatric brain tumors. Current Hh inhibitors face the challenge of drug resistance and tumor relapse, urging new insights in the Hh pathway regulation. Our previous study revealed how PDE4D controls global levels of cAMP in the cytoplasm to positively regulate Hh signaling; in the present study we found that a specific isoform PDE4D3 is tethered to the centrosome by myomegalin, a centrosome/Golgi associated protein. Myomegalin loss dislocates PDE4D3 from the centrosome, leading to local PKA over-activation and inhibition of the Hh signaling, leaving other PKA-related pathways unaffected. Myomegalin loss suppresses the proliferation of granule neuron precursors, and blocks the growth of medulloblastoma in mouse model. Our findings specify a new regulatory mechanism of the Hh pathway, and highlight an exciting therapeutic avenue for Hh-related cancers with reduced side effects.

PDE4DIP contributes to colorectal cancer growth and chemoresistance through modulation of the NF1/RAS signaling axis

“…PDE4DIP has been described as a PDE4D-interacting protein that may regulate cAMP hydrolysis and PKA activation 6 . In medulloblastoma cells, PDE4DIP loss has been shown to mislocalize PDE4D3 from the centrosome, leading to local PKA overactivation 30 . In the current study, we found that PDE4DIP did not affect the activation of the PKA pathway in CRC cells.…”

“…Genomic loss/gain and rearrangement of PDE4DIP have been discovered in prostate cancer, glioma, pineoblastoma, and intimal sarcoma [26][27][28][29] . Moreover, two recent studies demonstrated that loss of Mmg (an alternatively spliced isoform of the PDE4DIP gene) suppresses the growth of medulloblastoma and that depletion of another speci c isoform of PDE4DIP leads to inhibition of cell proliferation and motility 30,31 . Together, these ndings suggest that PDE4DIP may play a critical role in cancer.…”

cAMP Signaling in Cancer: A PKA-CREB and EPAC-Centric Approach

“…This PDE4DIP function is necessary for cell stability at the leading edge of migrating cells, and its influence on tumor cell motility and proliferation is vital in tumor development [203]. PDE4DIP deficiency has also been demonstrated in a mouse model to limit the proliferation of granule neuron precursors and to inhibit the formation of medulloblastoma [204], highlighting its significance as an appealing target for the treatment of malignant diseases. Myomegalin antibodies have been found in the serum of patients with esophageal squamous cell carcinoma (SCC) and are linked to a better prognosis [205].…”

Control of the Hedgehog pathway by compartmentalized PKA in the primary cilium

“…When PDE4D is recruited to the cytoplasmic membrane where most cAMP is produced, cAMP is more effectively degraded, leading to enhanced Hh signaling (Ge et al, 2015;Williams et al, 2015). In addition, a signalosome that includes PDE4D3 and the scaffold protein Myomegalin was identified at the centrosome (Verde et al, 2001); Myomegalin loss dislocates PDE4D3 from the centrosome, which subsequently promotes local PKA activity and suppresses Hh signaling (Peng et al, 2021).…”

“…PDE4DIP), a centrosomal and Golgi scaffolding protein. Myomegalin knockout dislocates PDE4D3 from the centrosome, elevates local cAMP/PKA activity and attenuates Hh signaling (Peng et al, 2021). In renal epithelial cells, a protein complex comprising AC5/6, AKAP150, PKA and PDE4C was found to locate in the primary cilium (Choi et al, 2011).…”