Search

IASB の改訂版の概念フレームワークにおける新設章「表示及び開示」で，包括利益の概念が導入された。本稿の目的は，①当該新設章「表示及び開示」において，情報セットアプローチは採用されているか，②情報セットアプローチと包括利益の概念及び包括利益計算書はどのような関連性を有するか，以上を明らかにすることである。考察の結果，①に関して，「表示及び開示」における規定に情報セットアプローチの特質がみられた。②に関して，英国における包括利益の概念の導入と包括利益計算書の開発は，情報セットアプローチを構成する思考の導入と並行して行われたことが明らかとなった。以上より，IASB の単独開発となった概念フレームワークの「表示及び開示」に，英国の情報セットアプローチの影響が残存していると結論付けた。

Significance Human breast cancer develops after a long period of latency under premalignant conditions. Strategies to target the premalignant conditions have yet to materialize since the molecular mechanisms remain obscure. Here, we discovered that FRS2β, expressed in a subset of mammary epithelial cells, directly activates nuclear factor–κB (NF-κB) and drives the initiation and promotion of the stroma-rich premalignant conditions. The FRS2β-triggered activation of NF-κB takes place in the early endosomes, the organelles, which have not been believed to be a major place for NF-κB signaling. The endosome signaling should be a novel focus for targeting therapy for prevention of breast cancer. This work paves a new way to develop preventive strategies of breast tumor development., Although it is held that proinflammatory changes precede the onset of breast cancer, the underlying mechanisms remain obscure. Here, we demonstrate that FRS2β, an adaptor protein expressed in a small subset of epithelial cells, triggers the proinflammatory changes that induce stroma in premalignant mammary tissues and is responsible for the disease onset. FRS2β deficiency in mouse mammary tumor virus (MMTV)–ErbB2 mice markedly attenuated tumorigenesis. Importantly, tumor cells derived from MMTV-ErbB2 mice failed to generate tumors when grafted in the FRS2β-deficient premalignant tissues. We found that colocalization of FRS2β and the NEMO subunit of the IκB kinase complex in early endosomes led to activation of nuclear factor–κB (NF-κB), a master regulator of inflammation. Moreover, inhibition of the activities of the NF-κB–induced cytokines, CXC chemokine ligand 12 and insulin-like growth factor 1, abrogated tumorigenesis. Human breast cancer tissues that express higher levels of FRS2β contain more stroma. The elucidation of the FRS2β–NF-κB axis uncovers a molecular link between the proinflammatory changes and the disease onset.

The neuronal cytoskeleton is responsible for governing dynamics such as neurite extension and cortex development. In particular, microtubules (MTs) and their associated proteins, and molecular motors, have been shown to be critical in many neuronal processes such as intracellular molecular transport and neuron differentiation. The fibroblast growth factors (FGFs) act as powerful morphogens that have been shown to play a role in regulating cortical development. FGFs activate receptor tyrosine kinases, of which fibroblast growth factor receptor substrate 3(FRS3) has been shown to interact with, to mediate downstream signaling cascades (regulating cell proliferation and differentiation). In addition to FRS3’s role in signaling, preliminary evidence suggested that FRS3 is a novel MT binding protein, and also interacts with MT associated proteins and the molecular motor kinesin. Furthermore, FRS3’s expression has been shown to coincide with migrating cortical neurons from E12 cortical precursor cell cultures. This thesis hypothesized that FRS3 regulates the differentiation of neurons as well as post-mitotic neuron function by regulating MT stability and intracellular transport of cargo and organelles.The research presented here has addressed this hypothesis in a multi-disciplinary manner. First, FRS3’s MT binding properties and its interactions with various proteins involved in molecular transport within cortical and hippocampal neurons (including motors, adapters and cargo) were investigated. FRS3 was shown to interact with markers of migrating and post-mitotic neurons (acetylated alpha and Beta III tubulin, respectively), post-synaptic density scaffolding proteins (Shank 2 and 3), cargo (Flg/FGFR1), molecular motor components (Kinesin Heavy Chain and Kinesin Light Chain), synaptic vesicle proteins (Syntaxin I and Synaptophysin) and finally MT associated proteins (MAP2, Doublecortin and Tau). Next, loss of FRS3 expression in SN56 cells resulted in increased sensitivity to the MT depolymerizing agent nocodazole, suggesting FRS3 is necessary for proper MT dynamics. Furthermore, loss of FRS3, but not the related signaling adaptor FRS2, resulted in impaired neurite outgrowth in both hippocampal and cortical cell culture. These results, taken together, suggest that FRS3, in addition to its role in FGF signaling, also interacts with members of the molecular transport machinery and confers stability to microtubules.

Background FGF receptor substrates (FRS2 and FRS3) are key adaptor proteins that mediate FGF-FGFR signalling in benign as well as malignant tissue. Here we investigated FRS2 and FRS3 as a means of disrupting global FGF signalling in prostate cancer. Methods FRS2 and FRS3 manipulation was investigated in vitro using over-expression, knockdown and functional assays. FRS2 and FRS3 expression was profiled in cell lines and clinical tumors of different grades. Results In a panel of cell lines we observed ubiquitous FRS2 and FRS3 transcript and protein expression in both benign and malignant cells. We next tested functional redundancy of FRS2 and FRS3 in prostate cancer cells. In DU145 cells, specific FRS2 suppression inhibited FGF induced signalling. This effect was not apparent in cells stably over-expressing FRS3. Indeed FRS3 over-expression resulted in enhanced proliferation (p = 0.005) compared to control cells. Given this functional redundancy, we tested the therapeutic principle of dual targeting of FRS2 and FRS3 in prostate cancer. Co-suppression of FRS2 and FRS3 significantly inhibited ERK activation with a concomitant reduction in cell proliferation (p < 0.05), migration and invasion (p < 0.05). Synchronous knockdown of FRS2 and FRS3 with exposure to cytotoxic irradiation resulted in a significant reduction in prostate cancer cell survival compared to irradiation alone (p < 0.05). Importantly, this synergistic effect was not observed in benign cells. Finally, we investigated expression of FRS2 and FRS3 transcript in a cohort of micro-dissected tumors of different grades as well as by immunohistochemistry in clinical biopsies. Here, we did not observe any difference in expression between benign and malignant biopsies. Conclusions These results suggest functional overlap of FRS2 and FRS3 in mediating mitogenic FGF signalling in the prostate. FRS2 and FRS3 are not over-expressed in tumours but targeted dual inhibition may selectively adversely affect malignant but not benign prostate cells.

We have investigated the signaling properties of the fibroblast growth factor (FGF) receptor substrate 3 (FRS3), also known as SNT-2 or FRS2β, in neurotrophin-dependent differentiation in comparison with the related adapter FRS2 (SNT1 or FRS2α). We demonstrate that FRS3 binds all neurotrophin Trk receptor tyrosine kinases and becomes tyrosine phosphorylated in response to NGF, BDNF, NT-3 and FGF stimulation in transfected cells and/or primary cortical neurons. Second, the signaling molecules Grb2 and Shp2 bind FRS3 at consensus sites that are highly conserved among FRS family members and that Shp2, in turn, becomes tyrosine phosphorylated. While FRS3 over-expression in PC12 cells neither increases NGF-induced neuritogenesis nor activation of Map kinase/AKT, comparable to previous reports on FRS2, over-expression of a chimeric adapter containing the PH/PTB domains of the insulin receptor substrate (IRS) 2, in place of the PTB domain of FRS3 (IRS2-FRS3) supports insulin-dependent Map kinase activation and neurite outgrowth in PC12 cells. Collectively, these data demonstrate that FRS3 supports ligand-induced Map kinase activation and that the chimeric IRS2-FRS3 adapter is stimulating sufficient levels of activated MapK to support neurite outgrowth in PC12 cells.