Signal for Survival

How does growth factor receptor signaling turn on survival processes? Well, that's still another syllabus, and then some. Let's boil it down to the essentials.

A ridiculous amount of work has made it clear that growth-factor mediated survival is highly dependent on an enzyme called PI3K, which stands for phosphatidylinositol-3-kinase. PI3K's job title tells the story: he phosphorylates phosphonositides. And that's pretty much it. But this one activity goes a long way, because those phosphoinositides in turn activate another kinase, Akt. And Akt is a most prodigious enzyme, at the very center of survival signaling--as well as a lot of other signaling.

Figure: Getting in on the Akt. Binding of growth factor (GF) causes dimerization and autophosphorylation of the receptor's cytoplasmic domain, resulting in activation of PI3K. By phosphorylating inositides (not shown), PI3K turns on Akt, which is usually bound to the inner membrane by a lipid moiety (gray zigzags). Akt is activated by dual phosphorylation and released from the membrane. It then phosphorylates substrates that lead to a wide range of metabolic activities, including survival signaling.

When you take a look at Akt's portfolio, you have to say "Wow. Are there any proteins this guy doesn't phosphorylate?" Well, yeah, there are, but to give you an idea of what I'm talking about, here's a partial list of just the survival substrates that Akt's involved with.

    1. Caspace 9 - by phosphorylating this upstream caspase, Akt can suppress caspase cascades.
    2. Apaf-1 - phosphorylation by Akt blocks participation in the apoptosome.
    3. IκB - this species inhibitis an important pro-survival transcription fact. Akt puts a stop to that.
    4. Bad - this pro-apoptotic Bcl-2 family protein is normally kept phosphorylated by Akt, which in turn keeps it sequestered in the cytosol.

        There are others. And as it happens, you lab has demonstrated that growth factor administration activates Akt by phosphorylation. That's cool enough, but what's especially good is the particular growth factor we used: insulin.