Abstract
ErbB2 and ErbB3, members of the EGF receptor/ErbB family, form a heterodimer upon binding of a ligand, inducing the activation of Rac small G protein and Akt protein kinase for cell movement and survival, respectively. The enhanced ErbB3/ErbB2 signaling causes tumorigenesis, invasion, and metastasis. We found here that the ErbB3/ErbB2 signaling is regulated by immunoglobulin-like Necl-2, which is down-regulated in various cancer cells and serves as a tumor suppressor. The extracellular region of ErbB3, but not ErbB2, interacted in cis with that of Necl-2. This interaction reduced the ligand-induced, ErbB2-catalyzed tyrosine phosphorylation of ErbB3 and inhibited the consequent ErbB3-mediated activation of Rac and Akt, resulting in the inhibition of cancer cell movement and survival. These inhibitory effects of Necl-2 were mediated by the protein-tyrosine phosphatase PTPN13 which interacted with the cytoplasmic tail of Necl-2. We describe here this novel mechanism for silencing of the ErbB3/ErbB2 signaling by Necl-2.
Highlights
Nositide 3-kinase (PI3K) and the subsequent activation of Rac small G protein and Akt protein kinase [2]
A Mechanism for Silencing the ErbB3/ErbB2 Signaling highly expressed during the neuronal differentiation of embryonic carcinoma cells [19]; SgIGSF was identified as a gene expressed in spermatogenic cells during the early stages of spermatogenesis [18]; TSLC1 was identified as a tumor suppressor in human non-small cell lung cancer [17]; and SynCAM1 was identified as a brain-specific synaptic adhesion molecule [15]
FLAG-tagged nectin-like molecule (Necl)-2 (FLAG-Necl-2) or FLAG alone and each member of the ErbB family were co-expressed in HEK293 cells, and the cells were cultured in suspension
Summary
Molecular Cloning of Mouse Necl-2, Necl-3, and Necl-4 cDNAs—To obtain the Necl-2, Necl-3, and Necl-4 cDNAs corresponding to GenBankTM/EMBL/DDBJ accession numbers AF434663, NM_178721, AY059394, respectively, we performed reverse transcription-PCR cloning. Assay for Activation of ErbB3 and Akt—A549 cells transfected with various expression vector and/or stealth RNAi were plated at a density of 3 ϫ 104 cells per square centimeter on dishes and cultured for 1 day. Cells were stimulated by DMEM containing 0.5% fatty acid-free BSA and 10 ng/ml HRG, and subjected to the assay for Rac activation. A549 cells co-transfected with pmaxGFP and empty vector or FLAG-Necl-2 expression vector (2 ϫ 104 cells) were plated on coverslips in 24-well culture plates and cultured with DMEM containing 0.5% fatty acid-free BSA in the presence or absence of 10 ng/ml HRG. A549 cells co-transfected with pmaxGFP and empty vector or FLAGNecl-2 and/or ErbB3 expression vector were cultured in suspension using a polyhydroxyethylmethacrylate-coated dish with DMEM containing 10 ng/ml HRG and 0.5% fatty acid-free BSA for 48 h.
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
