CrkII induces serum response factor activation and cellular transformation through its function in Rho activation.
CrkII belongs to the adaptor protein family that plays a crucial role in signal transduction. In order to better understand the biological functions of CrkII, we focused on the regulation of gene expression by CrkII. Various transcriptional control elements were examined for their activation by CrkII-expression, and we found that CrkII selectively activates the serum response element (SRE), a transcriptional control element of immediate-early genes. This SRE activation induced by CrkII-overexpression was mediated by the serum response factor (SRF) via Rho. Indeed, we confirmed that the amount of activated Rho was increased in the CrkII-expressing cells. Moreover, we showed that when overexpressed, CrkII induces the cellular transformation of NIH 3T3 cells and that a dominant negative mutant of Rho suppresses this transformation, strongly suggesting that activation of Rho is essential for the transforming activity by CrkII. Furthermore, we also found that CrkII and Galpha12, a member of the heterotrimeric G proteins, synergistically activates Rho as well as the SRF, and that an SH3 mutant of CrkII can inhibit the Galpha12-induced activation of SRF. These results strongly suggest that CrkII is involved in the activation of Rho and SRF by Galpha12. Our study provides strong evidence that Rho activation plays a crucial role in CrkII-mediated signals to induce gene expression and cellular transformation.
Iwahara
Toshinori
T
Laboratory of Molecular Oncology, Osaka Bioscience Institute, 6-2-4 Furuedai, Suita, Osaka 565-0874, Japan.
Akagi
Tsuyoshi
T
Shishido
Tomoyuki
T
Hanafusa
Hidesaburo
H
D016475:3T3 Cells / Q000378:metabolism / Q000473:pathology; D000818:Animals; D002471:Cell Transformation, Neoplastic; D044365:GTP-Binding Protein alpha Subunits, G12-G13; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D020962:Heterotrimeric GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D009154:Mutation; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D050737:Proto-Oncogene Proteins c-crk; D027602:Serum Response Element / Q000502:physiology*; D026362:Serum Response Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D015533:Transcriptional Activation; D020741:rho GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*
D011518:Proto-Oncogene Proteins; D050737:Proto-Oncogene Proteins c-crk; D026362:Serum Response Factor; D044365:GTP-Binding Protein alpha Subunits, G12-G13; D020962:Heterotrimeric GTP-Binding Proteins; D020741:rho GTP-Binding Proteins