SH3RF2 functions as an oncogene by mediating PAK4 protein stability

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 (PAK...

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Published in:Carcinogenesis (New York) 2014-03, Vol.35 (3), p.624-634
Main Authors: Kim, Tae Woo, Kang, Yun Kyung, Park, Zee Yong, Kim, Young-Ho, Hong, Seong Woo, Oh, Su Jin, Sohn, Hyun Ahm, Yang, Suk-Jin, Jang, Ye Jin, Lee, Dong Chul, Kim, Se-Yong, Yoo, Hyang-Sook, Kim, Eunhee, Yeom, Young Il, Park, Kyung Chan
Format: Article
Language:English
Subjects:
Base Sequence
Carrier Proteins - physiology
Cell Line
DNA Primers
Female
Humans
Male
Middle Aged
Oncogene Proteins - physiology
Oncogenes
p21-Activated Kinases - physiology
Protein Stability
Real-Time Polymerase Chain Reaction
Reverse Transcriptase Polymerase Chain Reaction
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Summary: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.
ISSN:0143-3334
1460-2180
DOI:10.1093/carcin/bgt338