Hrs is associated with STAM, a signal-transducing adaptor molecule. Its suppressive effect on cytokine-induced cell growth.
We previously reported a new type of signal-transducing adaptor molecule, STAM, which was shown to be involved in cytokine-mediated intracellular signal transduction. In this study, we molecularly cloned a 110-kDa phosphotyrosine protein inducible by stimulation with interleukin 2 (IL-2). The 110-kDa molecule was found to be a human counterpart of mouse Hrs (hepatocyte growth factor-regulated tyrosine kinase substrate) and to be associated with STAM. Tyrosine phosphorylation of Hrs is induced rapidly after stimulation with IL-2 and granulocyte-macrophage colony-stimulating factor as well as hepatocyte growth factor. The mutual association sites of Hrs and STAM include highly conserved coiled-coil sequences, suggesting that their association is mediated by the coiled-coil structures. Exogenous introduction of the wild-type Hrs significantly suppressed DNA synthesis upon stimulation with IL-2 and granulocyte-macrophage colony-stimulating factor, while the Hrs mutant deleted of the STAM-binding site lost such suppressive ability. These results suggest that Hrs counteracts the STAM function which is critical for cell growth signaling mediated by the cytokines.
Asao
H
H
Department of Microbiology and Immunology, Tohoku University School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-77, Japan.
Sasaki
Y
Y
Arita
T
T
Tanaka
N
N
Endo
K
K
Kasai
H
H
Takeshita
T
T
Endo
Y
Y
Fujita
T
T
Sugamura
K
K
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D019556:COS Cells; D002460:Cell Line; D002871:Chromosome Banding; D003001:Cloning, Molecular; D004261:DNA Replication; D056827:Endosomal Sorting Complexes Required for Transport; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism; D006801:Humans; D007376:Interleukin-2 / Q000378:metabolism; D053614:Janus Kinase 2; D053616:Janus Kinase 3; D051379:Mice; D008969:Molecular Sequence Data; D008970:Molecular Weight; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins; D015398:Signal Transduction; D016335:Zinc Fingers; D018909:src Homology Domains
D048868:Adaptor Proteins, Signal Transducing; D056827:Endosomal Sorting Complexes Required for Transport; D007376:Interleukin-2; D010750:Phosphoproteins; D011518:Proto-Oncogene Proteins; C109775:STAM protein, human; C491648:Stam protein, mouse; C096164:hepatocyte growth factor-regulated tyrosine kinase substrate; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D011505:Protein-Tyrosine Kinases; C507924:JAK2 protein, human; C507933:JAK3 protein, human; C507926:Jak2 protein, mouse; C507935:Jak3 protein, mouse; D053614:Janus Kinase 2; D053616:Janus Kinase 3