The cysteine-cluster motif of c-Yes, Lyn and FAK as a suppressive module for the kinases.
The Src family of non-receptor protein tyrosine kinases plays a critical role in the progression of human cancers so that the development of its specific inhibitors is important as a therapeutic tool. We previously reported that cysteine residues in the cysteine-cluster (CC) motif of v-Src were critical for the kinase inactivation by the SH-alkylating agents such as N-(9-acridinyl) maleimide (NAM), whereas other cysteine residues were dispensable. We found similar CC-motifs in other Src-family kinases and a non-Src-family kinase, FAK. In this study, we explored the function of the CC-motif in Yes, Lyn and FAK. While Src has four cysteines in the CC-motif, c-Yes and Lyn have three and two of the four cysteines, respectively. Two conserved cysteines of the Src family kinases, corresponding to Cys487 and Cys498 of Src, were essential for the resistance to the inactivation of the kinase activity by NAM, whereas the first cysteine of c-Yes, which is absent in Lyn, was less important. FAK has similar CC-motifs with two cysteines and both cysteines were again essential for the resistance to the inactivation of the kinase activity by NAM. Taken together, modification of cysteine residues of the CC-motif causes a repressor effect on the catalytic activity of the Src family kinases and FAK.
Rahman
Mohammad Aminur
MA
Division of Cancer Biology, Nagoya University School of Medicine, Nagoya 466-8550, Japan.
Senga
Takeshi
T
Oo
Myat Lin
ML
Hasegawa
Hitoki
H
Biswas
Md Helal Uddin
MH
Mon
Naing Naing
NN
Huang
Pengyu
P
Ito
Satoko
S
Yamamoto
Tadashi
T
Hamaguchi
Michinari
M
D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D017124:Conserved Sequence; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000737:chemistry* / Q000378:metabolism; D008301:Maleimides / Q000494:pharmacology; D008969:Molecular Sequence Data; D051575:Proto-Oncogene Proteins c-yes / Q000737:chemistry* / Q000378:metabolism; D013329:Structure-Activity Relationship; D019061:src-Family Kinases / Q000737:chemistry* / Q000378:metabolism
D008301:Maleimides; C080490:N-(9-acridinyl)maleimide; D051416:Focal Adhesion Protein-Tyrosine Kinases; D051575:Proto-Oncogene Proteins c-yes; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases