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The catalytic subunit of phosphoinositide 3-kinase: requirements for oncogenicity
1Department of Molecular and Experimental Medicine, The Scripps Research Institute, BCC239, La Jolla, California 92037, USA.
Abstract:
The retroviral oncogene p3k (v-p3k) of avian sarcoma virus 16 (ASV16) codes for the catalytic subunit of phosphoinositide (PI) 3-kinase, p110alpha. The v-P3k protein is oncogenic in vivo and in vitro; its cellular counterpart, c-P3k, lacks oncogenicity. Fusion of viral Gag sequences to the amino terminus of c-P3k activates the transforming potential. Activation can also be achieved by the addition of a myristylation signal to the amino terminus or of a farnesylation signal to the carboxyl terminus of c-P3k. A mutated myristylation signal was equally effective; it also caused a strong increase in the kinase activity of P3k. Mutations that inactivate lipid kinase activity abolish oncogenicity. The transforming activity of P3k is correlated with the ability to induce activating phosphorylation in Akt. Point mutations and amino-terminal deletions recorded in v-P3k were shown to be irrelevant to the activation of oncogenic potential. Interactions of P3k with the regulatory subunit of PI 3-kinase, p85, or with Ras are not required for transformation. These results support the conclusion that the oncogenicity of P3k depends on constitutive lipid kinase activity. Akt is an important and probably essential downstream component of the oncogenic signal from P3k.
Insights
The retroviral oncogene v-P3k, the catalytic subunit of phosphoinositide 3-kinase, is oncogenic due to its constitutive lipid kinase activity. This activity is essential for transforming cells and likely involves the downstream signaling of Akt.
Area of Science:
- Molecular Biology
- Oncology
- Virology
Background:
- The retroviral oncogene v-P3k from ASV16 encodes the p110alpha catalytic subunit of phosphoinositide 3-kinase (PI 3-kinase).
- While v-P3k is oncogenic, its cellular counterpart, c-P3k, is not; suggesting specific modifications confer oncogenicity.
Purpose of the Study:
- To investigate the mechanisms by which v-P3k gains oncogenic potential.
- To determine the role of lipid kinase activity and downstream signaling pathways in v-P3k-mediated transformation.
Main Methods:
- Investigated the oncogenic potential of modified c-P3k constructs, including those with viral Gag sequences, myristylation, or farnesylation signals.
- Assessed the impact of mutations inactivating lipid kinase activity on oncogenicity.
- Examined the correlation between v-P3k activity and Akt phosphorylation.
- Studied the requirement of interactions with p85 or Ras for transformation.
Main Results:
- Fusion of Gag sequences or addition of lipid modification signals (myristylation/farnesylation) to c-P3k activated its transforming potential.
- Mutations inactivating PI 3-kinase lipid activity abolished oncogenicity.
- v-P3k's transforming activity strongly correlated with its ability to induce activating phosphorylation in Akt.
- Interactions with p85 or Ras were not necessary for transformation.
Conclusions:
- The oncogenicity of v-P3k is dependent on its constitutive lipid kinase activity.
- Akt is a crucial downstream signaling component in the oncogenic pathway initiated by v-P3k.