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Inositol 1,4,5-trisphosphate (I[P.sub.3]) receptors (I[P.sub.3]Rs) are I[P.sub.3]-gated [Ca.sup.2+] channels that are located on intracellular [Ca.sup.2+] stores. We previously identified an I[P.sub.3]R binding protein, termed I[P.sub.3]R binding protein released with I[P.sub.3] (IRBIT). Because IRBIT is released from I[P.sub.3]R by physiological concentrations of I[P.sub.3], we hypothesized that IRBIT is a signaling molecule that is released from I[P.sub.3]R and regulates downstream target molecules in response to the production of I[P.sub.3]. Therefore, in this study, we attempted to identify the target molecules of IRBIT, and we succeeded in identifying [Na.sup.+]/HC[O.sup.-.sub.3] cotransporter 1 (NBC1) as an IRBIT binding protein. Of the two major splicing variants of NBC1, pancreas-type NBC1 (pNBC1) and kidney-type NBC1 (kNBC1), IRBIT was found to bind specifically to pNBC1 and not to bind to kNBC1. IRBIT binds to the N-terminal pNBC1-specific domain, and its binding depends on the phosphorylation of multiple serine residues of IRBIT. Also, an electrophysiological analysis in Xenopus oocytes revealed that pNBC1 requires coexpression of IRBIT to manifest substantial activity comparable with that of kNBC1, which displays substantial activity independently of IRBIT. These results strongly suggest that pNBC1 is the target molecule of IRBIT and that IRBIT has an important role in pH regulation through pNBC1. Also, our findings raise the possibility that the regulation through IRBIT enables NBC1 variants to have different physiological roles. pH | acidosis | phosphorylation

Transforming growth factor-β (TGF-β) regulates many aspects of cellular function. A member of the mitogen-activated protein kinase kinase kinase (MAPKKK) family, TAK1, was previously identified as a mediator in the signaling pathway of TGF-β superfamily members. The yeast two-hybrid system has now revealed two human proteins, termed TAB1 and TAB2 (for TAK1 binding protein), that interact with TAK1. TAB1 and TAK1 were co-immunoprecipitated from mammalian cells. Overproduction of TAB1 enhanced activity of the plasminogen activator inhibitor 1 gene promoter, which is regulated by TGF-β, and increased the kinase activity of TAK1. TAB1 may function as an activator of the TAK1 MAPKKK in TGF-β signal transduction., The mitogen-activated protein kinase (MAPK) pathway is a conserved eukaryotic signaling module that converts receptor signals into various outputs. This pathway includes three protein kineses: MAPKKK, MAPKK, and MAPK; MAPK [...]

The mitogen-activated protein kinase (MAPK) pathway is a conserved eukaryotic signaling module that converts receptor signals into various outputs. MAPK is activated through phosphorylation by MAPK kinase (MAPKK), which is first activated by MAPKK kinase (MAPKKK). A genetic selection based on a MAPK pathway in yeast was used to identify a mouse protein kinase (TAK1) distinct from other members of the MAPKKK family. TAK1 was shown to participate in regulation of transcription by transforming growth factor-o (TGF-β). Furthermore, kinase activity of TAK1 was stimulated in response to TGF-P and bone morphogenetic protein. These results suggest that TAK1 functions as a mediator in the signaling pathway of TGF-β superfamily members., Activation of MAPKs after ligand binding to various receptors has been correlated with numerous cellular responses, including proliferation, differentiation, and regulation of specific metabolic pathways in differentiated cell types. The [...]

The serine phosphorylation of STAT3 induced by TAK1-NLK (TGF-beta-activated kinase-Nemo-like kinase) cascade that is essential for TGF (transforming growth factor)-beta mediated mesoderm induction in Xenopus embryo is reported. The findings provide the first evidence that TAK1-NLK-STAT3 cascade participates in TGF-beta-mediated mesoderm induction.

Inositol 1,4,5-trisphosphate (IP3) receptors (IP3Rs) are IP3-gated Ca2+ channels that are located on intracellular Ca2+ stores. We previously identified an IP3R binding protein, termed IP3R binding protein released with IP3 (IRBIT). Because IRBIT is released from IP3R by physiological concentrations of IP3, we hypothesized that IRBIT is a signaling molecule that is released from IP3R and regulates downstream target molecules in response to the production of IP3. Therefore, in this study, we attempted to identify the target molecules of IRBIT, and we succeeded in identifying Na+/HCO3- cotransporter 1 (NBC1) as an IRBIT binding protein. Of the two major splicing variants of NBC1, pancreas-type NBC1 (pNBC1) and kidney-type NBC1 (kNBC1), IRBIT was found to bind specifically to pNBC1 and not to bind to kNBC1. IRBIT binds to the N-terminal pNBC1-specific domain, and its binding depends on the phosphorylation of multiple serine residues of IRBIT. Also, an electrophysiological analysis in Xenopus oocytes revealed that pNBC1 requires coexpression of IRBIT to manifest substantial activity comparable with that of kNBC1, which displays substantial activity independently of IRBIT. These results strongly suggest that pNBC1 is the target molecule of IRBIT and that IRBIT has an important role in pH regulation through pNBC1. Also, our findings raise the possibility that the regulation through IRBIT enables NBC1 variants to have different physiological roles. [ABSTRACT FROM AUTHOR]

Ligand-induced activation of epidermal growth factor receptor (EGFR) initiates trafficking events that re-localize the receptor from the cell surface to intracellular endocytic compartments. EGFR-containing endosomes are transported to lysosomes for degradation by the dynein-dynactin motor protein complex. However, this cargo-dependent endosomal trafficking mechanism remains largely uncharacterized. Here, we show that GTP-bound Rab7 is phosphorylated on S72 by leucine-rich repeat kinase 1 (LRRK1) at the endosomal membrane. This phosphorylation promotes the interaction of Rab7 (herein referring to Rab7a) with its effector RILP, resulting in recruitment of the dynein-dynactin complex to Rab7-positive vesicles. This, in turn, facilitates the dynein-driven transport of EGFR-containing endosomes toward the perinuclear region. These findings reveal a mechanism regulating the cargo-specific trafficking of endosomes., Competing Interests: Competing interestsThe authors declare no competing or financial interests., (© 2019. Published by The Company of Biologists Ltd.)