ErbB2 is an oncogene receptor tyrosine kinase linked to breast cancer. It is a member of the epidermal growth factor receptor (EGFR) minifamily. ErbB2 is currently viewed as an orphan receptor since, by itself, it does not bind EGF-like ligands and can be activated only when overexpressed in malignant cells or complexed with ErbB3, another member of the EGFR minifamily. Here, we report that ErbB2 can be activated by extracellular application of mildly alkaline (pH 8–9) media to ErbB2-transfected cells. We also show that the activation of the ErbB2 receptor by alkali is dose-dependent and buffer-independent. The endogenous ErbB2 receptor of A431 cell line can also undergo alkali-dependent autophosphorylation. Thus, we describe a novel ligand-independent mechanism of ErbB2 receptor activation.
Abstract—
Neurexins are a family of synaptic adhesion proteins that play a key role in synapse formation and maintenance. Neurexins undergo extensive alternative splicing at six sites (SS1–SS6) resulting in expression of multiplicity of different isoforms. Alternative splicing regulates the functional activity of neurexins in different types of tissues and cells and presumably plays a key role in determining the specificity of the interaction of various neurons. In this study, we have investigated the pattern of tissue expression of neurexin-1α mRNA isoforms including an insert in the recently discovered splice site SS6 using TaqMan Real-Time PCR in different organs of Wistar rats. The isoform containing the insert in the SS6 site was found only in neural tissues suggesting its potential functional importance. Position of the SS6 insert in the hinge region between the LNS5 and LNS6 domains increases variability of possible conformations of the molecule which may represent an additional mechanism for regulating functional activity of the neurexin-1α in the brain.
The orphan insulin receptor-related receptor (IRR) encoded by insrr gene is the third member of the insulin receptor family, also including the insulin receptor (IR) and the insulin-like growth factor receptor (IGF-1R). IRR is the extracellular alkaline medium sensor. In mice, insrr is expressed only in small populations of cells in specific tissues, which contain extracorporeal liquids of extreme pH. In particular, IRR regulates the metabolic bicarbonate excess in the kidney. In contrast, the role of IRR during Xenopus laevis embryogenesis is unknown, although insrr is highly expressed in frog embryos. Here, we examined the insrr function during the Xenopus laevis early development by the morpholino-induced knockdown. We demonstrated that insrr downregulation leads to development retardation, which can be restored by the incubation of embryos in an alkaline medium. Using bulk RNA-seq of embryos at the middle neurula stage, we showed that insrr downregulation elicited a general shift of expression towards genes specifically expressed before and at the onset of gastrulation. At the same time, alkali treatment partially restored the expression of the neurula-specific genes. Thus, our results demonstrate the critical role of insrr in the regulation of the early development rate in Xenopus laevis.
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