title: SH3RF2 functions as an oncogene by mediating PAK4 protein stability.
abstract: SH3RF (SH3-domain-containing RING finger protein) family members, SH3RF1-3, are multidomain scaffold proteins involved in promoting cell survival and apoptosis. In this report, we show that SH3RF2 is an oncogene product that is overexpressed in human cancers and regulates p21-activated kinase 4 (PAK4) protein stability. Immunohistochemical analysis of 159 colon cancer tissues showed that SH3RF2 expression levels are frequently elevated in cancer tissues and significantly correlate with poor prognostic indicators, including increased invasion, early recurrence and poor survival rates. We also demonstrated that PAK4 protein is degraded by the ubiquitin-proteasome system and that SH3RF2 inhibits PAK4 ubiquitination via physical interaction-mediated steric hindrance, which results in the upregulation of PAK4 protein. Moreover, ablation of SH3RF2 expression attenuates TRADD (TNFR-associated death domain) recruitment to tumor necrosis factor-α (TNF-α) receptor 1 and hinders downstream signals, thereby inhibiting NF-κB (nuclear factor-kappaB) activity and enhancing caspase-8 activity, in the context of TNF-α treatment. Notably, ectopic expression of SH3RF2 effectively prevents apoptosis in cancer cells and enhances cell migration, colony formation and tumor growth in vivo. Taken together, our results suggest that SH3RF2 is an oncogene that may be a definitive regulator of PAK4. Therefore, SH3RF2 may represent an effective therapeutic target for cancer treatment.
authors.affiliation: Medical Genomics Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 305-806, Korea.
authors.forename: Tae Woo
authors.initials: TW
authors.lastname: Kim
authors.forename: Yun Kyung
authors.initials: YK
authors.lastname: Kang
authors.forename: Zee Yong
authors.initials: ZY
authors.lastname: Park
authors.forename: Young-Ho
authors.initials: YH
authors.lastname: Kim
authors.forename: Seong Woo
authors.initials: SW
authors.lastname: Hong
authors.forename: Su Jin
authors.initials: SJ
authors.lastname: Oh
authors.forename: Hyun Ahm
authors.initials: HA
authors.lastname: Sohn
authors.forename: Suk-Jin
authors.initials: SJ
authors.lastname: Yang
authors.forename: Ye Jin
authors.initials: YJ
authors.lastname: Jang
authors.forename: Dong Chul
authors.initials: DC
authors.lastname: Lee
authors.forename: Se-Yong
authors.initials: SY
authors.lastname: Kim
authors.forename: Hyang-Sook
authors.initials: HS
authors.lastname: Yoo
authors.forename: Eunhee
authors.initials: E
authors.lastname: Kim
authors.forename: Young Il
authors.initials: YI
authors.lastname: Yeom
authors.forename: Kyung Chan
authors.initials: KC
authors.lastname: Park
mesh_terms: D001483:Base Sequence; D002352:Carrier Proteins / Q000502:physiology*; D002460:Cell Line; D017931:DNA Primers; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D015513:Oncogene Proteins / Q000502:physiology*; D009857:Oncogenes; D055550:Protein Stability; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D054462:p21-Activated Kinases / Q000502:physiology*
chemical_list: D002352:Carrier Proteins; D017931:DNA Primers; D015513:Oncogene Proteins; C588270:SH3RF2 protein, human; C116367:PAK4 protein, human; D054462:p21-Activated Kinases