Specific inhibition of NGF receptor tyrosine kinase activity by K-252a.
An involvement of protein tyrosine kinase in the transduction of the signals initiated by nerve growth factor (NGF) was investigated. A tyrosine kinase inhibitor, herbimycin, inhibited neurite outgrowth of rat pheochromocytoma PC12 cells induced by NGF but not that by dibutyryl-cAMP. Herbimycin and genistein blocked NGF-dependent activation of ras p21 whose essential function in neuronal differentiation has been reported. These observations suggested that tyrosine kinase activity is involved in the signaling pathways. K-252a, by contrast, inhibited NGF-induced but not EGF-dependent activation of ras p21. Tyrosine kinase activity of gp140trk, a constituent of NGF receptor, is activated by NGF for much a longer period compared to the activation of EGF receptor autokinase activity by EGF. We further demonstrated that autophosphorylation of gp140trk is selectively inhibited by K-252a.
Muroya
K
K
Division of Biochemistry and Cellular Biology, National Institute of Neuroscience, NCNP, Tokyo, Japan.
Hashimoto
Y
Y
Hattori
S
S
Nakamura
S
S
D000310:Adrenal Gland Neoplasms / Q000648:ultrastructure; D000595:Amino Acid Sequence; D000818:Animals; D016227:Benzoquinones; D003994:Bucladesine / Q000494:pharmacology; D002227:Carbazoles / Q000494:pharmacology*; D006023:Glycoproteins / Q000378:metabolism; D026121:Indole Alkaloids; D047029:Lactams, Macrocyclic; D008969:Molecular Sequence Data; D009414:Nerve Growth Factors / Q000494:pharmacology; D015689:Oncogene Protein p21(ras) / Q000378:metabolism; D010673:Pheochromocytoma / Q000648:ultrastructure; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011809:Quinones / Q000494:pharmacology; D051381:Rats; D011956:Receptors, Cell Surface / Q000378:metabolism*; D017475:Receptors, Nerve Growth Factor; D017828:Rifabutin / Q000031:analogs & derivatives; D015398:Signal Transduction; D014407:Tumor Cells, Cultured
D016227:Benzoquinones; D002227:Carbazoles; C033904:GP 140; D006023:Glycoproteins; D026121:Indole Alkaloids; D047029:Lactams, Macrocyclic; D009414:Nerve Growth Factors; D011809:Quinones; D011956:Receptors, Cell Surface; D017475:Receptors, Nerve Growth Factor; D017828:Rifabutin; D003994:Bucladesine; C020754:herbimycin; C049985:staurosporine aglycone; D011505:Protein-Tyrosine Kinases; D015689:Oncogene Protein p21(ras)