FRS2beta, a potential prognostic gene for non-small cell lung cancer, encodes a feedback inhibitor of EGF receptor family members by ERK binding.
An adaptor protein FRS2beta inhibits epidermal growth factor-receptor (EGFR) tyrosine kinase without being phosphorylated at tyrosine residues after EGF stimulation. Although binding to ERK appears to be important for this inhibition, the precise molecular mechanisms and the role of FRS2beta in signal transduction mediated by other EGFR family members, as well as its role in human cancer, remain unclear. In this study, we demonstrate that FRS2beta inhibits anchorage-independent cell growth induced by oncogenic ErbB2, another member of EGFR family, and that it inhibits heterodimer formation between EGFR and ErbB2. We mapped the residues important for the FRS2beta and ERK interaction to two docking (D) domain-like sequences on FRS2beta and two aspartic acid residues in the common docking (CD) domain of ERK. Moreover, in response to EGF, ERK translocated to the plasma membrane in cells expressing FRS2beta but not an FRS2beta mutant in which four arginine residues in the D domains were replaced with alanines, suggesting that FRS2beta serves as a plasma membrane anchor for activated ERK. Finally, a low mRNA expression level of FRS2beta was significantly correlated with poor prognosis in a cohort of 60 non-small cell lung cancer patients. Therefore, we have identified the molecular mechanisms by which FRS2beta acts as a feedback inhibitor of EGFR family members and suggest a role for FRS2beta as a tumor suppressor.
Department of Systems Biomedical Technology, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo, Japan.
D
D
Iejima
Y
Y
Minegishi
K
K
Takenaka
A
A
Siswanto
M
M
Watanabe
L
L
Huang
T
T
Watanabe
F
F
Tanaka
M
M
Kuroda
N
N
Gotoh
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics* / Q000378:metabolism; D002289:Carcinoma, Non-Small-Cell Lung / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D018929:Cell Culture Techniques; D002455:Cell Division; D002462:Cell Membrane / Q000201:enzymology; D003114:Colony-Forming Units Assay; D004789:Enzyme Activation; D004815:Epidermal Growth Factor / Q000494:pharmacology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007700:Kinetics; D008175:Lung Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D019814:Myristic Acid / Q000378:metabolism; D011379:Prognosis; D011485:Protein Binding; D012333:RNA, Messenger / Q000235:genetics
D048868:Adaptor Proteins, Signal Transducing; C113566:FRS3 protein, human; D012333:RNA, Messenger; D019814:Myristic Acid; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D048049:Extracellular Signal-Regulated MAP Kinases; D048052:Mitogen-Activated Protein Kinase 3