Signals on the move

A hallmark feature of eukaryotic cells is their intricate subcellular membrane compartmentalization, which biochemically and spatially isolates cellular processes including signal transduction, protein synthesis, and energy production. Membrane-spanning proteins such as growth factor receptors are transported through these compartments by the actions of a host of membrane binding proteins that bend, pinch and move bits of cargo-containing membrane from one compartment to another. Growth factor receptors change their signaling properties as they transit through these different compartments, and so cells can turn growth factor signaling up or down by regulating the rate of transit. The challenge is to understand how networks of hundreds of interacting membrane deforming proteins work to control cargo traffic, and how these proteins might themselves be regulated by the cell to reroute cargo.

Live imaging of dynamic interactions between subcellular compartments in fly neurons.
(click to watch movie)

Now, in a recent study published in the Journal of Cell Biology, new Biology faculty member Avital Rodal, together with Troy Littleton at MIT, identify a novel interaction between two membrane-binding proteins, Nervous Wreck (Nwk) and Sorting Nexin 16 (SNX16), that are critical for controlling the traffic of growth factor receptors that drive the expansion of neuronal arbors. Using the neurons that innervate muscles in fruit fly larvae as a model, Rodal and colleagues show that a physical association between these two proteins is necessary to turn off signaling by receptors that have been previously activated by growth factors. Perplexingly, though Nwk and SNX16 must physically interact to execute their role in driving membrane movements, they appear to reside in different subcellular compartments, in different locations within the neuron. To solve this conundrum, Rodal and colleagues took advantage of the spinning disk confocal microscope in the Brandeis Correlative Light and Electron Microscopy facility to look at the dynamic behavior of these compartments in living neurons in larvae. They found that the two distinct compartments inhabited by Nwk and SNX16 undergo dynamic and transient interactions, which represent the point in space and time that signaling receptor cargo is transferred between compartments. These receptor trafficking events are implicated in diseases ranging from neurodegenerative disease to mental retardation and addiction, underlining the health importance of understanding how signal transduction is modulated by intracellular membrane traffic in neurons.

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