CELL BIOLOGY OF THE NEURON Polarity ... - Tavernarakis Lab

Cell Biology of the Neuron: Polarity, Plasticity and Regeneration, Crete 2011
JNK-Induced Changes in Axonal Transport are
mediated by the Bidirectional Co-regulator JIP1
Meng-meng Fu, Erika Holzbaur
University of Pennsylvania
The polarized morphology of the neuron requires the delivery of synaptic
proteins, the clearance of damaged or misfolded proteins and the relay of
neurotrophic as well as stress signals along the axon. The regulation of axonal
transport, however, is poorly understood. We propose that intracellular JNK (cjun
N-terminal kinase) signaling can modulate changes in organelle transport via
its scaffolding protein JIP1 (JNK-interacting protein). In neuronal cultures,
pharmacological inhibition of JNK reversibly arrests dense phase vesicle
transport in both directions while activation of JNK increases the speed of
retrograde transport. Live-cell imaging of neurons transfected with fluorescently
tagged vesicular markers indicates that cargos affected by JNK inhibition include
APP-positive and Rab7-positive vesicles. Targeted siRNA knockdown of JIP1
also decreases the velocity of transport of APP-positive and Lysotracker-positive
vesicles, implicating JIP1 as a candidate mediator of JNK-dependent changes in
axonal transport. JIP1 is known to associate with JNK, with vesicular
transmembrane proteins and with kinesin light chain (KLC). We now show in
coimmunoprecipitations that JIP1 additionally binds to the C-terminus of
p150Glued, a subunit of dynactin. KLC and p150Glued have distinct binding
sites within JIP1 and truncated JIP1 lacking the KLC-binding domain retains its
ability to bind to p150Glued. These observations support the role of JNK in
regulating transport at the cargo level via its scaffolding protein JIP1, which acts
as a bidirectional co-regulator of transport by binding to both anterograde and
retrograde motors.
Presented by: Fu, Meng-meng
Poster No 038
Green Session
120