Activation of the Ran GTPase is subject to growth factor regulation and can give rise to cellular transformation.
Although the small GTPase Ran is best known for its roles in nucleocytoplasmic transport, mitotic spindle assembly, and nuclear envelope formation, recent studies have demonstrated the overexpression of Ran in multiple tumor types and that its expression is correlated with a poor patient prognosis, providing evidence for the importance of this GTPase in cell growth regulation. Here we show that Ran is subject to growth factor regulation by demonstrating that it is activated in a serum-dependent manner in human breast cancer cells and, in particular, in response to heregulin, a growth factor that activates the Neu/ErbB2 tyrosine kinase. The heregulin-dependent activation of Ran requires mTOR (mammalian target of rapamycin) and stimulates the capped RNA binding capability of the cap-binding complex in the nucleus, thus influencing gene expression at the level of mRNA processing. We further demonstrate that the excessive activation of Ran has important consequences for cell growth by showing that a novel, activated Ran mutant is sufficient to transform NIH-3T3 cells in an mTOR- and epidermal growth factor receptor-dependent manner and that Ran-transformed cells form tumors in mice.
Ly
Thi K
TK
Department of Molecular Medicine, Cornell University, Ithaca, New York 14853, USA.
Wang
Jianbin
J
Pereira
Ryan
R
Rojas
Katherine S
KS
Peng
Xu
X
Feng
Qiyu
Q
Cerione
Richard A
RA
Wilson
Kristin F
KF
D000818:Animals; D001943:Breast Neoplasms / Q000201:enzymology* / Q000235:genetics; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000201:enzymology* / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D009154:Mutation; D041681:NIH 3T3 Cells; D020890:Neuregulin-1 / Q000378:metabolism* / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D039381:RNA Cap-Binding Proteins / Q000235:genetics / Q000378:metabolism; D012323:RNA Processing, Post-Transcriptional / Q000187:drug effects / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases; D020931:ran GTP-Binding Protein / Q000235:genetics / Q000378:metabolism*
D047908:Intracellular Signaling Peptides and Proteins; D020890:Neuregulin-1; D017346:Protein Serine-Threonine Kinases; D039381:RNA Cap-Binding Proteins; D012333:RNA, Messenger; D018719:Erb-b2 Receptor Tyrosine Kinases; D058570:TOR Serine-Threonine Kinases; D020931:ran GTP-Binding Protein; C094131:NRG1 protein, human; C490581:Nrg1 protein, mouse; C120587:RAN protein, human; C102460:Ran protein, mouse; C546842:MTOR protein, human; C546843:mTOR protein, mouse; C508053:ERBB2 protein, human; C524056:Erbb2 protein, mouse