title: PDE4D promotes FAK-mediated cell invasion in BRAF-mutated melanoma.
abstract: The cyclic AMP (cAMP) signaling pathway is critical in melanocyte biology for regulating differentiation. It is downregulated by phosphodiesterase (PDE) enzymes, which degrade cAMP itself. In melanoma evidence suggests that inhibition of the cAMP pathway by PDE type 4 (PDE4) favors tumor progression. For example, in melanomas harboring RAS mutations, the overexpression of PDE4 is crucial for MAPK pathway activation and proliferation induced by oncogenic RAS. Here we showed that PDE4D is overexpressed in BRAF-mutated melanoma cell lines, constitutively disrupting the cAMP pathway activation. PDE4D promoted melanoma invasion by interacting with focal adhesion kinase (FAK) through the scaffolding protein RACK1. Inhibition of PDE4 activity or inhibition of PDE4D interaction with FAK reduced invasion. PDE4D expression is increased in patients with advanced melanoma and PDE4D-FAK interaction is detectable in situ in metastatic melanoma. Our study establishes the role of PDE4D in BRAF-mutated melanoma as regulator of cell invasion, and suggests its potential as a target for preventing metastatic dissemination.
authors.affiliation: INSERM, U976, Centre de Recherche sur la Peau, F-75010 Paris, France.|Univ Paris Diderot, Sorbonne Paris Cité, UMR 976, F-75010 Paris, France.|Département de dermatologie, AP-HP, Hôpital Saint Louis, Paris, France.
authors.forename: J
authors.initials: J
authors.lastname: Delyon
authors.affiliation: INSERM, U976, Centre de Recherche sur la Peau, F-75010 Paris, France.|Univ Paris Diderot, Sorbonne Paris Cité, UMR 976, F-75010 Paris, France.
authors.forename: A
authors.initials: A
authors.lastname: Servy
authors.affiliation: INSERM, U976, Centre de Recherche sur la Peau, F-75010 Paris, France.|Univ Paris Diderot, Sorbonne Paris Cité, UMR 976, F-75010 Paris, France.
authors.forename: F
authors.initials: F
authors.lastname: Laugier
authors.affiliation: INSERM, U976, Centre de Recherche sur la Peau, F-75010 Paris, France.|Univ Paris Diderot, Sorbonne Paris Cité, UMR 976, F-75010 Paris, France.
authors.forename: J
authors.initials: J
authors.lastname: André
authors.affiliation: Département de Pathologie and INSERM U955 équipe 9, Hôpital Henri-Mondor, Assistance Publique-Hôpitaux de Paris (AP-HP), and Faculté de Médecine, Université Paris Est Créteil Val de Marne, Créteil, France.
authors.forename: N
authors.initials: N
authors.lastname: Ortonne
authors.affiliation: Département de Pathologie, AP-HP, Hôpital Saint Louis, and INSERM U1165, Université Paris Diderot, Sorbonne Paris Cité, Paris, France.
authors.forename: M
authors.initials: M
authors.lastname: Battistella
authors.affiliation: INSERM, U976, Centre de Recherche sur la Peau, F-75010 Paris, France.|Univ Paris Diderot, Sorbonne Paris Cité, UMR 976, F-75010 Paris, France.|AP-HP, Hôpital Saint Louis, Laboratoire de Pharmacologie, Paris, France.
authors.forename: S
authors.initials: S
authors.lastname: Mourah
authors.affiliation: INSERM, U976, Centre de Recherche sur la Peau, F-75010 Paris, France.|Univ Paris Diderot, Sorbonne Paris Cité, UMR 976, F-75010 Paris, France.
authors.forename: A
authors.initials: A
authors.lastname: Bensussan
authors.affiliation: INSERM, U976, Centre de Recherche sur la Peau, F-75010 Paris, France.|Univ Paris Diderot, Sorbonne Paris Cité, UMR 976, F-75010 Paris, France.|Département de dermatologie, AP-HP, Hôpital Saint Louis, Paris, France.
authors.forename: C
authors.initials: C
authors.lastname: Lebbé
authors.affiliation: INSERM, U976, Centre de Recherche sur la Peau, F-75010 Paris, France.|Univ Paris Diderot, Sorbonne Paris Cité, UMR 976, F-75010 Paris, France.
authors.forename: N
authors.initials: N
authors.lastname: Dumaz
mesh_terms: D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation; D002465:Cell Movement; D049109:Cell Proliferation; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000235:genetics / Q000378:metabolism*; D051417:Focal Adhesion Kinase 1 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008544:Melanocytes / Q000166:cytology / Q000378:metabolism; D008545:Melanoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D009154:Mutation / Q000235:genetics*; D009361:Neoplasm Invasiveness; D009367:Neoplasm Staging; D010766:Phosphorylation; D011379:Prognosis; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D015398:Signal Transduction; D014407:Tumor Cells, Cultured
chemical_list: D014408:Biomarkers, Tumor; D051417:Focal Adhesion Kinase 1; C496050:PTK2 protein, human; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; C517376:PDE4D protein, human