Activation of cellular p21ras by myristoylation.
p21ras is palmitoylated on a cysteine residue near the C-terminus. Changing Cys-186 to Ser in oncogenic forms produces a non-palmitoylated protein that fails to associate with membranes and does not transform NIH 3T3 cells. To examine whether palmitate acts in a general way to increase ras protein hydrophobicity, or is involved in more specific interactions between p21ras and membranes, we constructed genes that encode non-palmitoylated ras proteins containing myristic acid at their N-termini. Myristoylated, activated ras, without palmitate (61Leu/186Ser) exhibited both efficient membrane association and full transforming activity. Unexpectedly, we found that myristoylated forms of normal cellular ras were also potently transforming. Myristoylated c-ras retained the high GTP binding and GTPase characteristic of the cellular protein and, moreover, bound predominantly GDP in vivo. This implied that it continued to interact with GAP (GTPase-activating protein). While the membrane binding induced by myristate permitted transformation, only palmitate produced a normal (non-transforming) association of ras with membranes and must therefore regulate ras function by some unique property that myristate does not mimic. Myristoylation thus represents a novel mechanism by which the ras proto-oncogene protein can become transforming.
Buss
J E
JE
La Jolla Cancer Research Foundation, CA 92037.
Solski
P A
PA
Schaeffer
J P
JP
MacDonald
M J
MJ
Der
C J
CJ
D000215:Acylation; D000818:Animals; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism*; D051379:Mice; D009226:Myristates / Q000378:metabolism*; D009227:Myristic Acids / Q000378:metabolism*; D015689:Oncogene Protein p21(ras) / Q000502:physiology*; D010168:Palmitates / Q000378:metabolism
D009226:Myristates; D009227:Myristic Acids; D010168:Palmitates; D015689:Oncogene Protein p21(ras)