title: N terminus of ASPP2 binds to Ras and enhances Ras/Raf/MEK/ERK activation to promote oncogene-induced senescence.
abstract: The ASPP2 (also known as 53BP2L) tumor suppressor is a proapoptotic member of a family of p53 binding proteins that functions in part by enhancing p53-dependent apoptosis via its C-terminal p53-binding domain. Mounting evidence also suggests that ASPP2 harbors important nonapoptotic p53-independent functions. Structural studies identify a small G protein Ras-association domain in the ASPP2 N terminus. Because Ras-induced senescence is a barrier to tumor formation in normal cells, we investigated whether ASPP2 could bind Ras and stimulate the protein kinase Raf/MEK/ERK signaling cascade. We now show that ASPP2 binds to Ras-GTP at the plasma membrane and stimulates Ras-induced signaling and pERK1/2 levels via promoting Ras-GTP loading, B-Raf/C-Raf dimerization, and C-Raf phosphorylation. These functions require the ASPP2 N terminus because BBP (also known as 53BP2S), an alternatively spliced ASPP2 isoform lacking the N terminus, was defective in binding Ras-GTP and stimulating Raf/MEK/ERK signaling. Decreased ASPP2 levels attenuated H-RasV12-induced senescence in normal human fibroblasts and neonatal human epidermal keratinocytes. Together, our results reveal a mechanism for ASPP2 tumor suppressor function via direct interaction with Ras-GTP to stimulate Ras-induced senescence in nontransformed human cells.
authors.affiliation: Division of Hematology and Medical Oncology, Department of Medicine and the Knight Cancer Institute, Oregon Health and Science University, Portland, OR 97239, USA.
authors.forename: Zhiping
authors.initials: Z
authors.lastname: Wang
authors.forename: Yuangang
authors.initials: Y
authors.lastname: Liu
authors.forename: Maho
authors.initials: M
authors.lastname: Takahashi
authors.forename: Kathryn
authors.initials: K
authors.lastname: Van Hook
authors.forename: Kerstin M
authors.initials: KM
authors.lastname: Kampa-Schittenhelm
authors.forename: Brett C
authors.initials: BC
authors.lastname: Sheppard
authors.forename: Rosalie C
authors.initials: RC
authors.lastname: Sears
authors.forename: Philip J S
authors.initials: PJ
authors.lastname: Stork
authors.forename: Charles D
authors.initials: CD
authors.lastname: Lopez
mesh_terms: D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D016922:Cellular Senescence / Q000502:physiology*; D019281:Dimerization; D005347:Fibroblasts; D045325:HCT116 Cells; D006801:Humans; D015603:Keratinocytes; D020935:MAP Kinase Signaling System / Q000502:physiology*; D008856:Microscopy, Fluorescence; D010766:Phosphorylation; D010957:Plasmids / Q000235:genetics; D048493:Proto-Oncogene Proteins B-raf / Q000737:chemistry / Q000378:metabolism; D019908:Proto-Oncogene Proteins c-raf / Q000737:chemistry / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D018631:ras Proteins / Q000378:metabolism*
chemical_list: D051017:Apoptosis Regulatory Proteins; D034741:RNA, Small Interfering; C090468:TP53BP2 protein, human; D048493:Proto-Oncogene Proteins B-raf; D019908:Proto-Oncogene Proteins c-raf; D018631:ras Proteins