Negative control of the Myc protein by the stress-responsive kinase Pak2.
Pak2 is a serine/threonine kinase that participates in the cellular response to stress. Among the potential substrates for Pak2 is the protein Myc, encoded by the proto-oncogene MYC. Here we demonstrate that Pak2 phosphorylates Myc at three sites (T358, S373, and T400) and affects Myc functions both in vitro and in vivo. Phosphorylation at all three residues reduces the binding of Myc to DNA, either by blocking the requisite dimerization with Max (through phosphorylation at S373 and T400) or by interfering directly with binding to DNA (through phosphorylation at T358). Phosphorylation by Pak2 inhibits the ability of Myc to activate transcription, to sustain cellular proliferation, to transform NIH 3T3 cells in culture, and to elicit apoptosis on serum withdrawal. These results indicate that Pak2 is a negative regulator of Myc, suggest that inhibition of Myc plays a role in the cellular response to stress, and raise the possibility that Pak2 may be the product of a tumor suppressor gene.
Huang
Zhongdong
Z
The George Williams Hooper Foundation, University of California, San Francisco, California 94143-0552, USA. huangzd@itsa.ucsf.edu
Traugh
Jolinda A
JA
Bishop
J Michael
JM
D000818:Animals; D017209:Apoptosis; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D050976:Basic-Leucine Zipper Transcription Factors; D002453:Cell Cycle; D002460:Cell Line; D002471:Cell Transformation, Neoplastic; D004247:DNA / Q000037:antagonists & inhibitors / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D051379:Mice; D041681:NIH 3T3 Cells; D010766:Phosphorylation; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D000090063:Proto-Oncogene Mas; D016271:Proto-Oncogene Proteins c-myc / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D014157:Transcription Factors; D015533:Transcriptional Activation; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D054462:p21-Activated Kinases
D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D050976:Basic-Leucine Zipper Transcription Factors; D004268:DNA-Binding Proteins; C000715470:MAS1 protein, human; C499330:MAX protein, human; C067850:Myc associated factor X; D000090063:Proto-Oncogene Mas; D016271:Proto-Oncogene Proteins c-myc; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C068422:Max protein, mouse; D004247:DNA; C515907:PAK2 protein, human; C515909:Pak2 protein, mouse; D017346:Protein Serine-Threonine Kinases; D054462:p21-Activated Kinases