Hh-Np can be untethered from the plasma membrane of the secreting cell by ADAM17-mediated cleavage of the lipidated N- and C-termini (Dierker et al, 2009; Ohlig et al, 2011; Ohlig et al, 2012). Shedding of SHH Np from the plasma membrane is abrogated by siRNA depletion of ADAM17, as well as in the presence of metalloprotease inhibitors or mutation of the ADAM17 catalytic E406 residue (Dierker et al, 2009). ADAM17-mediated cleavage is stimulated by heparin sulphate and likely occurs in the context of a HSPG-SHH complex although specific HSPGs have not been identified (Dierker et al, 2009). Cleavage of the cholesterol- and palmitoyl-modified termini is suggested to promote a SHH conformation that is competent to bind to the Patched receptor (Ohlig et al, 2011).
Dierker, T, Dreier, R, Petersen, A, Bordych, C, Grobe, K
Ohlig, S, Farshi, P, Pickhinke, U, van den Boom, J, Höing, S, Jakuschev, S, Hoffmann, D, Dreier, R, Schöler, HR, Dierker, T, Bordych, C, Grobe, K
Ohlig, S, Pickhinke, U, Sirko, S, Bandari, S, Hoffmann, D, Dreier, R, Farshi, P, Götz, M, Grobe, K
metalloendopeptidase activity of ADAM17 [plasma membrane]
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