TY - JOUR
T1 - FKBP12 Binds to Acylated H-Ras and Promotes Depalmitoylation
AU - Ahearn, Ian M.
AU - Tsai, Frederick D.
AU - Court, Helen
AU - Zhou, Mo
AU - Jennings, Benjamin C.
AU - Ahmed, Mahiuddin
AU - Fehrenbacher, Nicole
AU - Linder, Maurine E.
AU - Philips, Mark R.
N1 - Funding Information:
This work was supported by National Institutes of Health (NIH) grants GM55279 (MRP), CA116034 (M.R.P.), CA118495 (M.R.P.), and GM51466 (M.E.L.); by an award from the Jeffrey Rosenzweig Foundation (M.R.P.); and by a predoctoral fellowship from the AHA Midwest Affiliate (B.C.J.). We thank Mattias Weiwad and Gunter Fischer (MPF for Enzymology of Protein Folding, Halle/Saale, Germany) for the kind gift of DM-CHX. We thank ARIAD Pharmaceuticals, Cambridge, MA, for supplying AP21967.
PY - 2011/1/21
Y1 - 2011/1/21
N2 - A cycle of palmitoylation/depalmitoylation of H-Ras mediates bidirectional trafficking between the Golgi apparatus and the plasma membrane, but nothing is known about how this cycle is regulated. We show that the prolyl isomerase (PI) FKBP12 binds to H-Ras in a palmitoylation-dependent fashion and promotes depalmitoylation. A variety of inhibitors of the PI activity of FKBP12, including FK506, rapamycin, and cycloheximide, increase steady-state palmitoylation. FK506 inhibits retrograde trafficking of H-Ras from the plasma membrane to the Golgi in a proline 179-dependent fashion, augments early GTP loading of Ras in response to growth factors, and promotes H-Ras-dependent neurite outgrowth from PC12 cells. These data demonstrate that FKBP12 regulates H-Ras trafficking by promoting depalmitoylation through cis-trans isomerization of a peptidyl-prolyl bond in proximity to the palmitoylated cysteines.
AB - A cycle of palmitoylation/depalmitoylation of H-Ras mediates bidirectional trafficking between the Golgi apparatus and the plasma membrane, but nothing is known about how this cycle is regulated. We show that the prolyl isomerase (PI) FKBP12 binds to H-Ras in a palmitoylation-dependent fashion and promotes depalmitoylation. A variety of inhibitors of the PI activity of FKBP12, including FK506, rapamycin, and cycloheximide, increase steady-state palmitoylation. FK506 inhibits retrograde trafficking of H-Ras from the plasma membrane to the Golgi in a proline 179-dependent fashion, augments early GTP loading of Ras in response to growth factors, and promotes H-Ras-dependent neurite outgrowth from PC12 cells. These data demonstrate that FKBP12 regulates H-Ras trafficking by promoting depalmitoylation through cis-trans isomerization of a peptidyl-prolyl bond in proximity to the palmitoylated cysteines.
UR - https://www.scopus.com/pages/publications/78651468721
U2 - 10.1016/j.molcel.2011.01.001
DO - 10.1016/j.molcel.2011.01.001
M3 - Article
C2 - 21255728
AN - SCOPUS:78651468721
SN - 1097-2765
VL - 41
SP - 173
EP - 185
JO - Molecular cell
JF - Molecular cell
IS - 2
ER -