A 15 amino acid stretch close to the Grb2-binding domain defines two differentially expressed hSos1 isoforms with markedly different Grb2 binding affinity and biological activity.
We compared structure, expression and functional properties of two hSos1 cDNA isoforms (IsfI and Isf II) isolated, respectively, from human fetal brain and adult skeletal muscle libraries. IsfI and IsfII nucleotide sequences differ only by the presence in IsfII of an inframe 45 hp insertion located near the first proline-rich motif required for Grb2 binding. Some human tissues express only one isoform whereas others express different proportions of both in fetal and adult stages. In vitro binding assays and in vivo functional studies showed that MI exhibits significantly higher Grb2 binding affinity and biological activity than IsfI. These results suggest that functionally different hSos1 isoforms, with differential tissue expression and distribution, play important regulatory roles in the mechanisms controlling Ras activation in different tissues and/or developmental stages.
Rojas
J M
JM
Laboratory of Cellular and Molecular Biology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
Coque
J J
JJ
Guerrero
C
C
Aroca
P
P
Font de Mora
J
J
de la Cruz
X
X
Lorenzi
M V
MV
Esteban
L M
LM
Santos
E
E
D048868:Adaptor Proteins, Signal Transducing; D000328:Adult; D000595:Amino Acid Sequence; D001483:Base Sequence; D001923:Brain Chemistry; D018076:DNA, Complementary / Q000737:chemistry*; D005333:Fetus; D051380:GRB2 Adaptor Protein; D005786:Gene Expression Regulation; D011905:Genes, ras / Q000235:genetics; D005982:Glutathione Transferase / Q000378:metabolism; D020662:Guanine Nucleotide Exchange Factors; D006801:Humans; D008969:Molecular Sequence Data; D018482:Muscle, Skeletal / Q000737:chemistry*; D010446:Peptide Fragments / Q000737:chemistry* / Q000378:metabolism; D017433:Protein Structure, Secondary; D011506:Proteins / Q000737:chemistry* / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D014158:Transcription, Genetic; D014162:Transfection; D015003:Yeasts / Q000201:enzymology; D001616:beta-Galactosidase / Q000096:biosynthesis; D020663:ras Guanine Nucleotide Exchange Factors
D048868:Adaptor Proteins, Signal Transducing; D018076:DNA, Complementary; D051380:GRB2 Adaptor Protein; C495948:GRB2 protein, human; D020662:Guanine Nucleotide Exchange Factors; D010446:Peptide Fragments; D011506:Proteins; D011993:Recombinant Fusion Proteins; D020663:ras Guanine Nucleotide Exchange Factors; D005982:Glutathione Transferase; D001616:beta-Galactosidase