Activation of the receptor tyrosine kinase ErbB4 leads to various cellular responses such as proliferation, survival, differentiation, and chemotaxis. Two pairs of naturally occurring ErbB4 isoforms differing in their juxtamembrane (JMa/JMb) and C termini (cyt1/cyt2) have been described. To examine the role of ErbB4 in neuron migration, we cloned and stably transfected each of the four ErbB4 isoforms in ST14A cells (a neural progenitor cell line derived from the striatum of embryonic day 14 rats) endogenously expressing the other members of the ErbB family: ErbB1, ErbB2, and ErbB3. Using immunoprecipitation assays, we showed that the neuregulin-11 (NRG11) stimulus induced ErbB4 tyrosine phosphorylation and phosphatidylinositol 3-kinase (PI3K) recruitment and activation (as demonstrated by Akt phosphorylation) either directly (ErbB4 cyt1 isoform) or indirectly (ErbB4 cyt2 isoform). We examined the ability of the four ErbB4 isoforms to induce chemotaxis and cell proliferation in response to NRG11 stimulation. Using migration assays, we observed that only ErbB4-expressing cells stimulated with NRG11 showed a significant increase in migration, whereas the growth rate remained unchanged. Additional assays showed that inhibition of PI3K (but not of phospholipase C␥) dramatically reduced migratory activity. Our data show that ErbB4 signaling via PI3K activation plays a fundamental role in controlling NRG11-induced migration.The ErbB receptor family consists of four receptor tyrosine kinases named the epidermal growth factor (EGF) 1 receptor, ErbB2, ErbB3, and ErbB4 (reviewed in Ref. 1). Ligand-dependent activation of ErbB receptors results in homo-or heterodimerization, which stimulates receptor trans-phosphorylation on cytoplasmic tyrosine residues, creating binding sites for adaptor or enzymatic proteins. EGF receptor and ErbB4 homodimers are active kinases in the absence of coreceptors, whereas ErbB3 (which has little or no intrinsic tyrosine kinase activity) and ErbB2 (for which no ligand has been identified) necessitate coreceptor interaction for signal transduction (2). Thus, whereas ErbB2 and ErbB3 are limited to heterodimerization, the EGF receptor and ErbB4 can be activated by either homo-or heterodimerization.An interesting ErbB4 feature (recently reviewed in Ref.3) is the existence of isoforms generated by alternative splicing (4). One isoform pair (5) is characterized by alternative splicing of exons located in the extracellular juxtamembrane region conferring (JMa), or not (JMb), susceptibility to proteolytic cleavage (6) by a member of the ADAM (a disintegrin and metalloprotease) family, the tumor necrosis factor-␣-converting enzyme (7). ErbB4 proteolytic cleavage produces a membraneassociated 80-kDa fragment that can be degraded by proteasome activity following polyubiquitination (8) or that can be the substrate for subsequent ␥-secretase cleavage, which releases the cytoplasmic domain from the membrane and allows, intriguingly, nuclear translocation of a fragment (9, 10) that can act as cotranscrip...
Rapid activation of PI3K, endothelial nitric oxide synthase and protein kinase G and a consequent improvement in diastolic calcium can be added to established Nrg1 protective roles.
It has previously been shown that, in the estrogen-receptor-positive breast-tumor cell lines T47D and ZR75.1, the erbB-2 protein and mRNA content are controlled negatively and positively by, respectively, estrogens and anti-estrogens. Since estrogens have a positive effect on cell proliferation, while anti-estrogens inhibit cell growth, the results suggested that there may be an inverse correlation between growth and erbB-2 expression. We have now examined this matter further. The effect of various growth-modulatory agents including estrogen (E2), progesterone (Pg), retinoic acid (RA), epidermal growth factor (EGF), insulin (Ins), prolactin (Prl), 12-O-tetradecanolyl-phorbol-13-acetate (TPA) and dibutyryl-3':5'-cyclic-AMP (cAMP) on c-erbB-2 promoter activity, RNA and protein expression have been examined. The growth stimulators E2 and EGF both reduced the level of erbB-2 protein. However, while E2 clearly repressed erbB-2 transcription, in the case of EGF, neither mRNA nor transcription were decreased. Of the agents which inhibit the growth of T47D and ZR75.1 cells--Pg, Prl, cAMP, RA and TPA--only Pg and cAMP caused an increase in the erbB-2 protein level. Pg and cAMP positively influenced c-erbB-2 promoter activity and RNA amount. TPA and RA also increased promoter activity but neither erbB-2 mRNA nor protein level was enhanced. The erbB-2 protein expression in cultures of T47D and ZR75.1 cells at different densities was also analyzed. Both the level of erbB-2 protein and c-erbB-2 promoter activity rose markedly in confluent cultures, suggesting a transcriptional mechanism of control. In conclusion, the data suggest that the effects of various agents on erbB-2 expression are complex and cannot be explained simply as reflecting the growth state of the cells.
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