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Title: Phosphorylation at Ser-181 of oncogenic KRAS is required for tumor growth
Author: Barceló, Carles
Paco, Noelia
Morell, Mireia
Alvarez-Moya, Blanca
Bota-Rabassedasa Neus
Jaumot i Pijoan, Montserrat
Vilardell Villellas, Felip
Capellá, G. (Gabriel)
Agell i Jané, Neus
Keywords: Proteïnes
Transport biològic
Biological transport
Issue Date: 26-Dec-2013
Publisher: American Association for Cancer Research
Abstract: KRAS phosphorylation has been reported recently to modulate the activity of mutant KRAS protein in vitro. In this study, we defined S181 as a specific phosphorylation site required to license the oncogenic function of mutant KRAS in vivo. The phosphomutant S181A failed to induce tumors in mice, whereas the phosphomimetic mutant S181D exhibited an enhanced tumor formation capacity, compared with the wild-type KRAS protein. Reduced growth of tumors composed of cells expressing the nonphosphorylatable KRAS S181A mutant was correlated with increased apoptosis. Conversely, increased growth of tumors composed of cells expressing the phosphomimetic KRAS S181D mutant was correlated with increased activation of AKT and ERK, two major downstream effectors of KRAS. Pharmacologic treatment with PKC inhibitors impaired tumor growth associated with reduced levels of phosphorylated KRAS and reduced effector activation. In a panel of human tumor cell lines expressing various KRAS isoforms, we showed that KRAS phosphorylation was essential for survival and tumorigenic activity. Furthermore, we identified phosphorylated KRAS in a panel of primary human pancreatic tumors. Taken together, our findings establish that KRAS requires S181 phosphorylation to manifest its oncogenic properties, implying that its inhibition represents a relevant target to attack KRAS-driven tumors.
Note: Versió postprint del document publicat a:
It is part of: Cancer Research, 2013, vol. 74, num. 4, p. 1190-1199
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ISSN: 0008-5472
Appears in Collections:Articles publicats en revistes (Biomedicina)

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