Proteolysis Connects p75 to the Cytoskeleton

Science's STKE  21 Jun 2005:
Vol. 2005, Issue 289, pp. tw225
DOI: 10.1126/stke.2892005tw225

The neurotrophin receptor p75 interacts with multiple partners, leading to diverse cellular responses (see Ceni and Barker). One of these receptor complexes mediates myelin inhibition through myelin-associated glycoprotein (MAG), a Nogo-A fragment (Nogo-66), and oligodendrocyte-myelin glycoprotein (OMgp). Domeniconi et al. show that treatment of primary cerebellar neurons with a soluble MAG triggered proteolytic processing of p75. Regulated intramembrane and juxtamembrane proteolysis by α-secretase and then by γ-secretase appeared to be responsible for the induced cleavage of p75. Addition of specific inhibitors of the proteasome along with inhibitors of γ-secretase or protein kinase C (PKC) led to accumulation of the juxtamembrane cleavage fragment (30 kD), suggesting that γ-secretase cleavage may be dependent on PKC. Addition of the γ-secretase inhibitor or the PKC inhibitor to the cultured cells blocked the ability of MAG to inhibit neurite outgrowth. Expression of the intracellular domain (ICD) of p75 inhibited neurite outgrowth of NG108 cells even in the absence of MAG, and expression of uncleavable forms of p75 resulted in the inability of the cells to be inhibited by MAG. MAG-induced activation of Rho was also blocked by inhibitors of α-secretase, γ-secretase, or PKC, thus confirming that signaling to this regulator of the actin cytoskeleton involves regulated intramembrane proteolysis.

C. Ceni, P. A. Barker, Getting RIP'd stunts your growth. Neuron 46, 839-844 (2005). [PubMed]

M. Domeniconi, N. Zampieri, T. Spencer, M. Hilaire, W. Mellado, M. V. Chao, M. T. Filbin, MAG induces regulated intramembrane proteolysis of the p75 neurotrophin receptor to inhibit neurite outgrowth. Neuron 46, 849-855 (2005). [PubMed]