Phosphodiesterase 4D acts downstream of Neuropilin to control Hedgehog signal transduction and the growth of medulloblastoma

Abstract

Alterations in Hedgehog (Hh) signaling lead to birth defects and cancers including medulloblastoma, the most common pediatric brain tumor. Although inhibitors targeting the membrane protein Smoothened suppress Hh signaling, acquired drug resistance and tumor relapse call for additional therapeutic targets. Here we show that phosphodiesterase 4D (PDE4D) acts downstream of Neuropilins to control Hh transduction and medulloblastoma growth. PDE4D interacts directly with Neuropilins, positive regulators of Hh pathway. The Neuropilin ligand Semaphorin3 enhances this interaction, promoting PDE4D translocation to the plasma membrane and cAMP degradation. The consequent inhibition of protein kinase A (PKA) enhances Hh transduction. In the developing cerebellum, genetic removal of Neuropilins reduces Hh signaling activity and suppresses proliferation of granule neuron precursors. In mouse medulloblastoma allografts, PDE4D inhibitors suppress Hh transduction and inhibit tumor growth. Our findings reveal a new regulatory mechanism of Hh transduction, and highlight PDE4D as a promising target to treat Hh-related tumors.DOI: http://dx.doi.org/10.7554/eLife.07068.001

Hedgehog Signal Transduction: Key Players, Oncogenic Drivers, and Cancer Therapy

“…For example, production of cAMP by adenylyl cyclase and degradation of cAMP by phosphodiesterases can promote and attenuate PKA activity, respectively. Recently, degradation of cAMP was mechanistically linked to signaling by transmembrane neuropilin (Nrp) receptors (Ge et al, 2015). The Nrp ligand Semaphorin3 (Sema3) promotes interaction of phosphodiesterase 4D (PDE4D) with the Nrp cytoplasmic domain.…”

“…For instance, phosphodiesterase inhibitors may block cAMP degradation and thereby increase activity of the negative Hh pathway regulator PKA. In vivo phosphodiesterase inhibition was shown to oppose the growth of Smo inhibitor resistant MB (Ge et al, 2015) as well as Shh-MB driven by loss of Gnas (He et al, 2014b). In considering these alternatives, demonstration of target specificity and/or specificity for Shh-dependent tumors will be important.…”

Myomegalin regulates Hedgehog pathway by controlling PDE4D at the centrosome

“…It is a challenge to specifically control PKA activities in the Hh signaling while keeping other pathways unaffected. Our previous study pointed PDE4D as a potential target to inhibit Hh signaling 15 . Our current study is based on an established view in the field of PDE4D-cAMP that distinct PDE4D isoforms are localized to discrete subcellular compartments, where they locally tailor cAMP levels for specific cellular events 18 .…”

“…PKA activity relies on the concentration of cAMP, which is precisely balanced by adenylyl cyclase that produces cAMP, and phosphodiesterase (PDE) that degrades cAMP. In our previous studies, we found that PDE4D, recruited to the cytoplasmic membrane by sema3-Neuropilin signaling, governs cAMP levels in the entire cell to regulate Hh signaling 14,15 . Our results were corroborated by Williams et al who independently discovered PDE4D as a positive regulator of the Hh pathway in a chemical genetic screen in zebrafish 16 .…”

Development of thieno- and benzopyrimidinone inhibitors of the Hedgehog signaling pathway reveals PDE4-dependent and PDE4-independent mechanisms of action

“…In addition to our studies with EGM1, mounting evidence has linked PDE4 to Hh signaling and tumorigenesis. 29,30 Therefore, we viewed EGM1 as a starting point for in vitro probe development toward an optimized downstream of Sufu Hh inhibitor; however, EGM1’s limited aqueous solubility and modest potency required improvement.…”