Kinetic mechanisms of mutation-dependent Harvey Ras activation and their relevance for the development of Costello syndrome.
Costello syndrome is linked to activating mutations of a residue in the p-loop or the NKCD/SAK motifs of Harvey Ras (HRas). More than 10 HRas mutants that induce Costello syndrome have been identified; G12S HRas is the most prevalent of these. However, certain HRas p-loop mutations also are linked to cancer formation that are exemplified with G12V HRas. Despite these relations, specific links between types of HRas mutations and diseases evade definition because some Costello syndrome HRas p-loop mutations, such as G12S HRas, also often cause cancer. This study established novel kinetic parameter-based equations that estimate the value of the cellular fractions of the GTP-bound active form of HRas mutant proteins. Such calculations differentiate between two basic kinetic mechanisms that populate the GTP-bound form of Ras in cells. (i) The increase in the level of GTP-bound Ras is caused by the HRas mutation-mediated perturbation of the intrinsic kinetic characteristics of Ras. This generates a broad spectrum of the population of the GTP-bound form of HRas that typically causes Costello syndrome. The upper end of this spectrum of HRas mutants, as exemplified by G12S HRas, can also cause cancer. (ii) The increase in the level of GTP-bound Ras occurs because the HRas mutations perturb the action of p120GAP on Ras. This causes production of a significantly high population of the only GTP-bound form of HRas linked merely to cancer formation. HRas mutant G12V belongs to this category.
Department of Chemistry and Biochemistry, The University of Texas at Arlington , Arlington, Texas 76019, United States.
Michael
M
Wey
Jungwoon
J
Lee
Soon Seog
SS
Jeong
Jungho
J
Kim
Jongyun
J
Heo
D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D001665:Binding Sites; D055162:Biocatalysis; D056685:Costello Syndrome / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism; D004789:Enzyme Activation; D006153:Guanosine Diphosphate / Q000378:metabolism; D006160:Guanosine Triphosphate / Q000378:metabolism; D006801:Humans; D006868:Hydrolysis; D007700:Kinetics; D051379:Mice; D008969:Molecular Sequence Data; D050505:Mutant Proteins / Q000378:metabolism; D041681:NIH 3T3 Cells; D017433:Protein Structure, Secondary; D016283:Proto-Oncogene Proteins p21(ras) / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D015398:Signal Transduction; D020729:p120 GTPase Activating Protein / Q000235:genetics / Q000378:metabolism; D020666:ras-GRF1 / Q000235:genetics / Q000378:metabolism
D050505:Mutant Proteins; C557248:RASA1 protein, human; C513039:RASGRF1 protein, human; D011994:Recombinant Proteins; D020729:p120 GTPase Activating Protein; D020666:ras-GRF1; D006153:Guanosine Diphosphate; D006160:Guanosine Triphosphate; C501009:HRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras)