CMT 2B: Rab7 Mutants Associated with CMT Disease Exhibit Enhanced NGF-St

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PLoS One. 2010 Dec 9;5(12):e15351.

Rab7 Mutants Associated with Charcot-Marie-Tooth Disease Exhibit Enhanced

NGF-Stimulated Signaling.

Basuray S, Mukherjee S, Romero E, MC, Wandinger-Ness A.

Department of Pathology and Cancer Research and Treatment Center, University of

New Mexico Health Sciences Center, Albuquerque, New Mexico, United States of

America.

Abstract

Missense mutants in the late endosomal Rab7 GTPase cause the autosomal dominant

peripheral neuropathy Charcot-Marie-Tooth disease type 2B (CMT2B). As yet, the

pathological mechanisms connecting mutant Rab7 protein expression to altered

neuronal function are undefined.

Here, we analyze the effects Rab7 CMT2B mutants on nerve growth factor (NGF)

dependent intracellular signaling in PC12 cells. The nerve growth factor

receptor TrkA interacted similarly with Rab7 wild-type and CMT2B mutant

proteins, but the mutant proteins significantly enhanced TrkA phosphorylation in

response to brief NGF stimulation. Two downstream signaling pathways (Erk1/2 and

Akt) that are directly activated in response to phospho-TrkA were differentially

affected.

Akt signaling, arising in response to activated TrkA at the plasma membrane was

unaffected. However Erk1/2 phosphorylation, triggered on signaling endosomes,

was increased. Cytoplasmic phospho-Erk1/2 persisted at elevated levels relative

to control samples for up to 24 h following NGF stimulation. Nuclear shuttling

of phospho Erk1/2, which is required to induce MAPK phosphatase expression and

down regulate signaling, was greatly reduced by the Rab7 CMT2B mutants and

explains the previously reported inhibition in PC12 neurite outgrowth.

In conclusion, the data demonstrate a mechanistic link between Rab7 CMT2B

mutants and altered TrkA and Erk1/2 signaling from endosomes.