A central oncogenic signaling cascade where activation state–not expression–predicts patient outcomes.
Receptor tyrosine kinases (RTKs) activate PI3K, which phosphorylates PIP2 to generate PIP3 at the plasma membrane. PIP3 recruits Akt via its PH domain, where it undergoes activating phosphorylation at T308 and S473. Active Akt phosphorylates numerous substrates controlling survival (BAD), cell cycle (p27), and metabolism (GSK3²).
PTENLoading... dephosphorylates PIP3, opposing PI3K. PTEN loss or PIK3CA activating mutations drive constitutive pathway activation in many cancers.
The Signaling Chain: Growth signals → PI3K → PIP3 → Akt → mTOR and other targets. This pathway promotes cell survival, growth, and metabolism.
Regulation: PTEN normally keeps this pathway in check by removing PIP3. When PTEN is lost, the pathway becomes overactive.
Conventional biomarkers measure phospho-Akt (pT308, pS473) by IHCLoading.... But phosphorylation status doesn't fully capture activation. The conformational change when Akt binds PIP3 can be detected by FRETLoading...–reporting on the membrane recruitment step that initiates activation.
In breast cancerLoading... and ccRCCLoading..., FRET-measured Akt-PIP3 interaction correlates with survival while phospho-Akt expression does not. This demonstrates that conformational/interaction state provides superior functional information.
Beyond Genetics: Genetic tests can identify PIK3CA mutations, PTEN loss, etc. But genetics tells you what COULD happen; functional measurement tells you what IS happening.
QF-Pro Connection: The validated Akt activation assay provides a functional readout of PI3K pathway activity, regardless of which upstream alteration is driving it.
