title: RIO kinase 3 acts as a SUFU-dependent positive regulator of Hedgehog signaling.
abstract: Suppressor of fused (SUFU) is an essential negative regulator of the mammalian Hedgehog (HH) signaling pathway and its loss is associated with cancer development. On a cellular level, endogenous SUFU can mainly be detected in the cytoplasm and the nucleus. However, immunostaining of pancreatic cancer specimen revealed the existence of cell types showing selective enrichment of endogenous SUFU in the nucleus. Following up on this observation, we found that a SUFU construct which was experimentally tethered exclusively to the nucleus was unable to antagonize endogenous HH signaling, in contrast to control SUFU. These data suggest that alterations in the normal subcellular distribution of SUFU might interfere with its established negative role on the HH pathway. Performing a multi-well kinase screen in human cells identified RIO kinase 3 (RIOK3) as a novel modulator of SUFU subcellular distribution. Functionally, RIOK3 acts as a SUFU-dependent positive regulator of HH signaling. Taken together, we propose that factors modulating the nucleo-cytoplasmic distribution of SUFU impact on the normal function of this tumor suppressing protein.
authors.affiliation: Philipps University, Institute of Molecular Biology and Tumor Research (IMT), Emil-Mannkopff-Str. 2, 35037 Marburg, Germany.
authors.forename: Melanie
authors.initials: M
authors.lastname: Tariki
authors.forename: Sarah Alexandra
authors.initials: SA
authors.lastname: Wieczorek
authors.forename: Philipp
authors.initials: P
authors.lastname: Schneider
authors.forename: Sebastian
authors.initials: S
authors.lastname: Bänfer
authors.forename: Sophie
authors.initials: S
authors.lastname: Veitinger
authors.forename: Ralf
authors.initials: R
authors.lastname: Jacob
authors.forename: Volker
authors.initials: V
authors.lastname: Fendrich
authors.forename: Matthias
authors.initials: M
authors.lastname: Lauth
mesh_terms: D000818:Animals; D019556:COS Cells; D002466:Cell Nucleolus / Q000378:metabolism; D002522:Chlorocebus aethiops; D057809:HEK293 Cells; D053823:Hedgehog Proteins / Q000378:metabolism*; D006801:Humans; D051379:Mice; D041681:NIH 3T3 Cells; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D012097:Repressor Proteins / Q000032:analysis / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D053823:Hedgehog Proteins; D012097:Repressor Proteins; C490764:SUFU protein, human; D017346:Protein Serine-Threonine Kinases; C534426:RIO kinase 3, human
keywords: GLI; GLI1; HH; Hedgehog; RIOK3; SHH; SUFU; Signal transduction; glioma-associated oncogene 1; hedgehog; right open reading frame kinase 3; sonic hedgehog; suppressor of fused