Activation of the guanine nucleotide exchange factor Dbl following ACK1-dependent tyrosine phosphorylation.
Signals triggered by diverse receptors modulate the activity of Rho family proteins, although the regulatory mechanism remains largely unknown. On the basis of their biochemical activity as guanine nucleotide exchange factors (GEFs), Dbl family proteins are believed to be implicated in the regulation of Rho family GTP-binding proteins in response to a variety of extracellular stimuli. Here we show that GEF activity of full-length proto-Dbl is enhanced upon tyrosine phosphorylation. When transiently coexpressed with the activated form of the non-receptor tyrosine kinase ACK1, a downstream target of Cdc42, Dbl became tyrosine-phosphorylated. In vitro GEF activity of Dbl toward Rho and Cdc42 was augmented following tyrosine phosphorylation. Moreover, accumulation of the GTP-bound form of Rho and Rac within the cell paralleled ACK-1-dependent tyrosine phosphorylation of Dbl. Consistently, activation of c-Jun N-terminal kinase downstream of Rho family GTP-binding proteins was also enhanced when Dbl was tyrosine-phosphorylated. Collectively, these findings suggest that the tyrosine kinase ACK1 may act as a regulator of Dbl, which in turn activates Rho family proteins.
Kato
J
J
Faculty of Bioscience, Tokyo Institute of Technology, Tokyohama, 226-8501, Japan.
Kaziro
Y
Y
Satoh
T
T
D000818:Animals; D019556:COS Cells; D002460:Cell Line; D004789:Enzyme Activation; D020662:Guanine Nucleotide Exchange Factors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014162:Transfection; D014443:Tyrosine / Q000378:metabolism; D020764:cdc42 GTP-Binding Protein / Q000235:genetics / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000235:genetics / Q000378:metabolism
D020662:Guanine Nucleotide Exchange Factors; C057811:MCF2 protein, human; D011518:Proto-Oncogene Proteins; D011994:Recombinant Proteins; D014443:Tyrosine; D011505:Protein-Tyrosine Kinases; C403262:TNK2 protein, human; D020764:cdc42 GTP-Binding Protein; D020742:rhoA GTP-Binding Protein