Horiguchi, K., Hanada, T.,Fukui, Y., and Chishti, A. H., (2006) Transport of PIP3 by GAKIN, a kinesin-3 family protein, regulates neuronal cell polarity. J Cell Biol., 174:425-36. PMCID: PMC2064238
A neuron is a highly polarized cell having a single axon and multiple dendrites to transmit the signal to the neighboring neurons. When a neuron starts extending multiple neurites from the cell body, one of the neurites is selected, rapidly elongates to become a single axon, while others become dendrites.
Then, how does the neuron select one neurite to become an axon? Why is it so special?
At the tip of the axon, signaling molecules are activated to induce cytoskeleton rearrangement, membrane raffling, and neurite extension. PIP3, a lipid second messenger, regulates these cellular events and is known to accumulate at the tip of the axon.
What is PIP3? PIP3 is a phospholipid on the membrane. An enzyme called PI3K adds the phosphate at the 3-position of the inositol ring of PIP2. PIP2 commonly exists in the cells at a small population, while PIP3 is produced temporarily upon stimulation of the cells with growth factors.
So, is PIP3 produced by PI3K at the tip of the neurites?
Yes, but it is not the only way to mediate the accumulation of PIP3 at the tip. PIP3 is caught by a PIP3-binding protein called Centaurin-α1/PIP3BP, which interacts with a kinesin KIF13B. Kinesins are the molecular motors moving on the microtubules. Microtubules and actin filaments are like highways and local roads in the cells. And molecular motors (such as kinesins, dyneins, and myosins) are like trucks transporting cargoes.
This video is showing the reconstituted system in vitro, where microtubules are labeled green, and the lipid vesicles containing PIP3 are labeled red. In the presence of KIF13B, the red vesicles (PIP3) are moving on the green highways (microtubules).
KIF13B functions to directly accumulate PIP3 at the tip!
Inhibiting the function of KIF13B by its dominant negative mutants inhibited the accumulation of PIP3 at the tip and axon determination in primary neurons. Please read the article to see more.
Abbreviation:
PIP3: phosphatidylinositol (3,4,5)-triphosphate
PIP2: phosphatidylinositol (4,5)-diphosphate
PI3K: phosphoinositide 3-kinase
KIF13B: kinesin family 13B
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