Oncogenic synergism between ErbB1, nucleolin, and mutant Ras.
Alterations in the ErbB family of growth factor receptors, their signaling components, and mutational activation of Ras proteins are major contributors to malignant transformation. Recently, mutant Ras was shown to be capable of activating ErbB receptors in a ligand-independent manner. Furthermore, it was observed that nucleolin, a transcriptional regulator and ribosome biogenesis factor, can bind both K-Ras and the cytoplasmic tail of ErbB receptors to enhance ErbB receptor activation. However, the functional significance of these interactions to cancer pathogenesis has not been probed. Here, we show that endogenous nucleolin interacts simultaneously in vivo with endogenous Ras and ErbB1 (EGFR) in cancer cells. The C-terminal 212 amino acids of nucleolin were determined to be sufficient to interact with ErbB1 and all Ras protein isoforms (H-, N-, and K-Ras). Nucleolin partially colocalizes with Ras at the plasma membrane. Moreover, activated but not wild-type Ras facilitates nucleolin interaction with ErbB1 and stabilizes ErbB1 receptor levels. Most importantly, these three oncogenes synergistically facilitate anchorage-independent cell growth in vitro and tumor growth in vivo. Our findings suggest strategies to target nucleolin as a general approach to inhibiting ErbB- and Ras-driven cancers.
Department of Neurobiology, Tel-Aviv University, Ramat-Aviv, Israel.
Keren
K
Farin
Sari
S
Schokoroy
Roni
R
Haklai
Ifat
I
Cohen-Or
Galit
G
Elad-Sfadia
Merit E
ME
Reyes-Reyes
Paula J
PJ
Bates
Adrienne D
AD
Cox
Yoel
Y
Kloog
Ronit
R
Pinkas-Kramarski
D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D051379:Mice; D008819:Mice, Nude; D018613:Microscopy, Confocal; D050505:Mutant Proteins / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D009374:Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D014183:Transplantation, Heterologous; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism*; D000097796:Nucleolin
D066246:ErbB Receptors; D049452:Green Fluorescent Proteins; D050505:Mutant Proteins; D010750:Phosphoproteins; D016601:RNA-Binding Proteins; D018631:ras Proteins; D000097796:Nucleolin