The SH4-Unique-SH3-SH2 domains dictate specificity in signaling that differentiate c-Yes from c-Src.
c-Src and c-Yes are highly homologous members of the Src family of non-receptor tyrosine kinases. The overall sequence similarity between c-Src and c-Yes allows them to perform many overlapping functions. However, the phenotypes of the c-src and c-yes knockout mice, and cells derived from them, are quite different, indicating functional specificity between the two proteins. Specifically, c-src-/- cells are deficient in several processes that require dynamic regulation of the actin cytoskeleton. In order to begin to understand why c-Yes is unable to compensate for c-Src signaling, we used a series of Src/Yes chimeras in which the non-catalytic functional domains of Src527F were replaced by those of c-Yes. Using chicken embryo fibroblasts as a model system, our results indicate that the c-Yes N-terminal SH4-Unique domains are sufficient to inhibit the ability of Src527F to alter cell morphology, induce actin filament rearrangements or stimulate motility or invasive potential. The data also indicate that the SH4-Unique-SH3-SH2 domains of c-Yes work cooperatively and prevent activation of signaling proteins associated with Src527F transformation, including activation of phosphatidylinositol 3-kinase, phosphorylation of c-Raf and Akt and downregulation of RhoA-GTP. These data indicate that c-Yes may not modulate signals associated with c-Src-induced changes in actin filament integrity and may explain why c-Yes fails to compensate for c-Src signaling in src-/- cells.
Department of Microbiology, Immunology, and Cell Biology, West Virginia University School of Medicine, PO Box 9300, Morgantown 26506, USA.
Justin M
JM
Summy
Yong
Y
Qian
Bing-Hua
BH
Jiang
Anne
A
Guappone-Koay
Amanda
A
Gatesman
Xianglin
X
Shi
Daniel C
DC
Flynn
D008841:Actin Cytoskeleton / Q000378:metabolism*; D000818:Animals; D000081247:CSK Tyrosine-Protein Kinase; D002465:Cell Movement / Q000235:genetics; D048429:Cell Size / Q000235:genetics; D002478:Cells, Cultured; D002642:Chick Embryo; D005347:Fibroblasts / Q000166:cytology / Q000201:enzymology; D015971:Gene Expression Regulation, Enzymologic / Q000235:genetics; D020935:MAP Kinase Signaling System / Q000235:genetics; D009361:Neoplasm Invasiveness / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases; D017434:Protein Structure, Tertiary / Q000235:genetics; D011505:Protein-Tyrosine Kinases / Q000172:deficiency* / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism; D051575:Proto-Oncogene Proteins c-yes; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics*; D020742:rhoA GTP-Binding Protein / Q000378:metabolism; D018909:src Homology Domains / Q000502:physiology*; D019061:src-Family Kinases
D000081247:CSK Tyrosine-Protein Kinase; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D019908:Proto-Oncogene Proteins c-raf; D051575:Proto-Oncogene Proteins c-yes; D011993:Recombinant Fusion Proteins; D020742:rhoA GTP-Binding Protein; D019061:src-Family Kinases