Smoothened-dependent and -independent pathways in mammalian noncanonical Hedgehog signaling

Autor(es)

Faria, Alessandra V. de S. ^{[1, 2]} ; Akyala, Adamu Ishaku ^{[1, 3]} ; Parikh, Kaushal ^[4] ; Brueggemann, Lois W. ^[5] ; Spek, C. Arnold ^[5] ; Cao, Wanlu ^[1] ; Bruno, Marco J. ^[1] ; Bijlsma, Maarten F. ^[5] ; Fuhler, Gwenny M. ^[1] ; Peppelenbosch, Maikel P. ^{[1, 4]}

Afiliação do(s) autor(es)

^[1] Univ Med Ctr Rotterdam, Erasmus MC, Dept Gastroenterol & Hepatol, POB 2040, NL-3000 CA Rotterdam - Netherlands

^[2] Univ Estadual Campinas, Dept Biochem & Tissue Biol, Biol Inst, BR-13083862 Campinas, SP - Brazil

^[3] Nasarawa State Univ, Dept Microbiol, Fac Nat & Appl Sci, Keffi, Nasarawa State - Nigeria

^[4] Univ Med Ctr Groningen, Dept Cell Biol, NL-9713 GZ Groningen - Netherlands

^[5] Acad Med Ctr, Ctr Expt & Mol Med, Room H2-257, Meibergdreef 9, NL-1105 AZ Amsterdam - Netherlands

• Tipo de documento: Artigo Científico
• Fonte: Journal of Biological Chemistry; v. 294, n. 25, p. 9787-9798, JUN 21 2019.
• Citações Web of Science: 0

Resumo

Hedgehog proteins are pivotal morphogens acting through a canonical pathway involving first activation of ligand binding to Patched followed by alleviation of Smoothened receptor inhibition, leading to activation of Gli transcription factors. Noncanonical Hedgehog signaling remains poorly characterized but is thought to be mainly dependent on Smoothened. However, Smoothened inhibitors have yielded only partial success in combating Hedgehog signal transduction-dependent cancer, suggesting that noncanonical Smoothened-independent pathways also are clinically relevant. Moreover, several Smoothened-dependent effects (e.g. neurite projection) do not require transcriptional activation, further suggesting biological importance of noncanonical Smoothened-dependent pathways. We comprehensively characterized the cellular kinome in Hedgehog-challenged murine WT and Smoothened(-/-) fibroblasts as well as Smoothened agonist-stimulated cells. A peptide assay-based kinome analysis (in which cell lysates are used to phosphorylate specific kinase substrates), along with endocytosis, Lucifer Yellow-based, and immunoblotting assays, identified an elaborate signaling network of both Smoothened-dependent and -independent pathways that mediates actin reorganization through Src-like kinases, activates various proinflammatory signaling cascades, and concomitantly stimulates Wnt and Notch signaling while suppressing bone morphogenetic protein (BMP) signaling. The contribution of noncanonical Smoothened-independent signaling to the overall effects of Hedgehog on cellular physiology appears to be much larger than previously envisioned and may explain the transcriptionally independent effects of Hedgehog signaling on cytoskeleton. The observation that Patched-dependent, Smoothened-independent, noncanonical Hedgehog signaling increases Wnt/Notch signaling provides a possible explanation for the failure of Smoothened antagonists in combating Hedgehog-dependent but Smoothened inhibitor-resistant cancer. Our findings suggest that inhibiting Hedgehog-Patched interaction could result in more effective therapies as compared with conventional Smoothened-directed therapies. (AU)

• Processo FAPESP: 18/00736-0 - Correlação de microRNA em amostras de fezes e plaquetas de pacientes com câncer gastrointestinal e proteína tirosina fosfatase ACP1: triagem em câncer coloretal
• Beneficiário: Alessandra Valéria de Sousa Faria
• Modalidade de apoio: Bolsas no Exterior - Estágio de Pesquisa - Doutorado