N terminus of ASPP2 binds to Ras and enhances Ras/Raf/MEK/ERK activation to promote oncogene-induced senescence

Zhiping Wang, Yuangang Liu, Maho Takahashi, Kathryn Van Hook, Kerstin M. Kampa-Schittenhelm, Brett Sheppard, Rosalie Sears, Philip Stork, Charles Lopez

Research output: Contribution to journalArticle

35 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)312-317
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume110
Issue number1
DOIs
StatePublished - Jan 2 2013

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Mitogen-Activated Protein Kinase Kinases
Guanosine Triphosphate
Oncogenes
ras Proteins
Neoplasms
Monomeric GTP-Binding Proteins
Dimerization
Keratinocytes
Protein Kinases
Carrier Proteins
Protein Isoforms
Fibroblasts
Phosphorylation
Cell Membrane
Apoptosis

ASJC Scopus subject areas

  • General

Cite this

N terminus of ASPP2 binds to Ras and enhances Ras/Raf/MEK/ERK activation to promote oncogene-induced senescence. / Wang, Zhiping; Liu, Yuangang; Takahashi, Maho; Van Hook, Kathryn; Kampa-Schittenhelm, Kerstin M.; Sheppard, Brett; Sears, Rosalie; Stork, Philip; Lopez, Charles.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 110, No. 1, 02.01.2013, p. 312-317.

Research output: Contribution to journalArticle

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AU - Kampa-Schittenhelm, Kerstin M.

AU - Sheppard, Brett

AU - Sears, Rosalie

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