Are Phosphoinositides "the center of the universe"?

(This is an intro to a n upcoming entry.)

When I was an undergrad, working in a lab at McGill, my then boss Morag Park would joke that Phosphoinositides were at the center of the universe.

What did she mean by that? Well inositol metabolism seemed to be involved in everything, including oncogenesis and cell migration the only two important cellular activities.

So what the hell is inositol, phosphoinositides and all those inositol metabolites? I'll make this simple and then overload your neocortex. Inositol is a sugar polyalcoholcyclohexane molecule. It's hydroxyl groups can be phosphorylated to form phosphoinositides. Up to 6 phosphates can be linked to Inositol's six hydroxyl groups ... if all of the hydroxyl groups get phosphorylated you end up with inositol-hexaphosphate, or IP6 (see image). Inositol can also be linked to diacylglecerol to form phosphatidyl-inositol (PI).

So how do they act? Basically inositol derivatives are some of the most important second messengers in the cell.

Nomenclature note:
I = Inositol.
PP or P before the I = Phosphatidyl diacyl glycerol (i.e. Inositol is linked to a lipid).
Px after the I = Phospho groups, where x stands for the # of phosphates. Sometimes the position of the phosphates are listed in brackets.

OK time to blow your brains. How are inositol derivatives inter-converted? Well look at this map:

Click here for a blowup.

So about two dozen enzymes are constantly modifying inositol derivatives. Diacyl linked derivative are membrane bound. Free Inositol floats around the cytoplasm.

One of the most important Inositol metabolites is PIP3(3,4,5). This molecule is involved in many signaling cascades. It is removed (or converted to PIP2) by the action of PTEN [reaction 3.1.3.67 in the KEGG map]. The gene that encodes PTEN is the second most mutated gene found in cancer cells (the most mutated gene is the famous p53). So it's damn important.

Another famous Inositol metabolite is IP3. This is produced by a lipase (phospholipase C; PLC) that converts PIP2 into IP3 and diacyl-glycerol (DAG). IP3 will diffuse in the cytosol and open all the calcium channels in the ER. Calcium then rushes from the ER into the cytosol and activates a billion other pathways. Meanwhile DAG (inconcert with calcium) activate protein kinase C that goes on to activate another gadzillion signaling pathways.

What else do phosphoinositides do? Well many many many of them can bind to certain protein modules. This binding usually activates some enzymatic activity in the protein and/or relocalizes the protein to the proper intracellular compartment. The most famous of these inositol binding modules is the plextrin homology domain. It turns out that in many cells, PIP2 and PIP3 are produced (and restricted to) the membrane that becomes the "front" of the cell (often referred to at the site of cell polarity). Plextrin domain containing proteins get recruited there and direct cells to rearrange their entire organization. Some plextrin containing proteins activate small G-proteins - the master regulators of cell shape. What this all adds up to is that cells "polarize" in the direction of the PIP rich membrane. Recently some researchers have come up with the theory that PIPs act to differentiate membranes. As in :"this is the part of the membrane that acts as the leading edge", "this is membrane that should be engulfed and sent to the endosomes", "this is membrane that needs to go from the endosomes back to the plasma membrane." As a result membranes can recruit the proper machinery to fufill these various tasks.

This is just the tip of the iceberg.

In an upcoming entry I'll tell you a weird story ... and it concerns IP6 and mRNA export. So until then don't forget, phosphoinositides are the center of the universe.