UCS15A, a non-kinase inhibitor of Src signal transduction.
Src tyrosine kinase plays key roles in signal transduction following growth factor stimulation and integrin-mediated cell-substrate adhesion. Since src-signal transduction defects are implicated in a multitude of human diseases, we have sought to develop new ways to identify small molecule inhibitors using a yeast-based, activated-src over-expression system. In the present study, we describe the identification of a unique src-signal transduction inhibitor, UCS15A. UCS15A was found to inhibit the src specific tyrosine phosphorylation of numerous proteins in v-src-transformed cells. Two of these phosphoproteins were identified as bona-fide src substrates, cortactin and Sam68. UCS15A differed from conventional src-inhibitors in that it did not inhibit the tyrosine kinase activity of src. In addition, UCS15A appeared to differ from src-destabilizing agents such as herbimycin and radicicol that destabilize src by interfering with Hsp90. Our studies suggest that UCS15A exerted its src-inhibitory effects by a novel mechanism that involved disruption of protein-protein interactions mediated by src. One of the biological consequences of src-inhibition by UCS15A was its ability to inhibit the bone resorption activity of osteoclasts in vitro. These data suggest that UCS15A may inhibit the bone resorption activity of osteoclasts, not by inhibiting src tyrosine kinase activity, but by disrupting the interaction of proteins associated with src, thereby modulating downstream events in the src signal transduction pathway.
Sharma
S V
SV
Tokyo Research Laboratories, Kyowa Hakko Kogyo Co., Ltd. 3-6-6 Asahi-cho, Machida-shi, Tokyo 194, Japan.
Oneyama
C
C
Yamashita
Y
Y
Nakano
H
H
Sugawara
K
K
Hamada
M
M
Kosaka
N
N
Tamaoki
T
T
D016475:3T3 Cells / Q000187:drug effects / Q000378:metabolism; D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001547:Benzaldehydes / Q000494:pharmacology*; D016227:Benzoquinones; D001862:Bone Resorption / Q000188:drug therapy*; D002471:Cell Transformation, Neoplastic; D051356:Cortactin; D004268:DNA-Binding Proteins; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016391:Genes, src / Q000502:physiology; D006801:Humans; D047029:Lactams, Macrocyclic; D007783:Lactones / Q000494:pharmacology; D018942:Macrolides; D008297:Male; D051379:Mice; D008840:Microfilament Proteins / Q000378:metabolism; D009924:Organ Culture Techniques; D010010:Osteoclasts / Q000187:drug effects*; D010766:Phosphorylation / Q000187:drug effects; D011809:Quinones / Q000494:pharmacology; D016601:RNA-Binding Proteins / Q000378:metabolism; D051381:Rats; D017828:Rifabutin / Q000031:analogs & derivatives; D015398:Signal Transduction / Q000187:drug effects*; D014443:Tyrosine / Q000378:metabolism; D019061:src-Family Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*
D048868:Adaptor Proteins, Signal Transducing; D000900:Anti-Bacterial Agents; D001547:Benzaldehydes; D016227:Benzoquinones; C495868:CTTN protein, human; D051356:Cortactin; C495869:Cttn protein, mouse; C495870:Cttn protein, rat; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; C489559:KHDRBS1 protein, human; C513253:Khdrbs1 protein, mouse; D047029:Lactams, Macrocyclic; D007783:Lactones; D018942:Macrolides; D008840:Microfilament Proteins; D011809:Quinones; D016601:RNA-Binding Proteins; C426883:UCS15A; D017828:Rifabutin; D014443:Tyrosine; C020754:herbimycin; D019061:src-Family Kinases; C035359:monorden