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Human genome has ten genes that are collectedly called Ras association domain family (RASSF). RASSF is composed of two subclasses, C-RASSF and N-RASSF. Both N-RASSF and C-RASSF encode Ras association domain-containing proteins and are frequently suppressed by DNA hypermethylation in human cancers. However, C-RASSF and N-RASSF are quite different. Six C-RASSF proteins (RASSF1-6) are characterized by a C-terminal coiled-coil motif named Salvador/RASSF/Hippo domain, while four N-RASSF proteins (RASSF7-10) lack it. C-RASSF proteins interact with mammalian Ste20-like kinases-the core kinases of the tumor suppressor Hippo pathway-and cross-talk with this pathway. Some of them share the same interacting molecules such as MDM2 and exert the tumor suppressor role in similar manners. Nevertheless, each C-RASSF protein has distinct characters. In this review, we summarize our current knowledge of how C-RASSF proteins play tumor suppressor roles and discuss the similarities and differences among C-RASSF proteins.

Membrane-associated guanylate kinase with an inverted arrangement of protein-protein interaction domains (MAGI)2 (also called synaptic scaffolding molecule (S-SCAM), atrophin-1-interacting protein 1, activin receptor-interacting protein 1) is a scaffold protein that binds a wide variety of receptors, cell adhesion molecules and signalling molecules. It also interacts with other scaffold proteins and adaptors, and forms a protein network that supports cell junctions. As it is highly expressed in brain, the study on its roles in synaptic organization initially preceded. However, mounting evidence indicates that MAGI2/S-SCAM functions as a tumour suppressor and plays essential roles to maintain the integrity of cell structures in non-neuronal tissues. We review the articles regarding to MAGI2/S-SCAM outside brain and discuss future perspectives for the research of MAGI family proteins., (© The Authors 2015. Published by Oxford University Press on behalf of the Japanese Biochemical Society. All rights reserved.)

Mammals have 10 RASSF proteins, which are characterized by the Ras-association (RA) domain. Among them, RASSF1 to RASSF6 have the Salvador/RASSF/Hippo (SARAH) domain and form the subclass C-terminal RASSF proteins. Drosophila genome has a single C-terminal RASSF, dRASSF. All these RASSF proteins are related to the tumor suppressive Hippo pathway, and are considered to function as tumor suppressors. Caenorhabditis elegans T24F1.3 encodes a protein with the RA and the SARAH domains. The amino acid sequences are 40% and 55% similar to those of RASSF1 in the RA and the SARAH domains, respectively. We have characterized T24F1.3 gene product and named it RSF-1 as RASSF1 homolog. RSF-1 is widely expressed in epithelial cells. About 14% rsf-1 mutants exhibit defects in embryonal morphogenesis and the actin disorganization. The combinatorial synthetic lethal analysis demonstrates that the lethality is enhanced to more than 80% in rsf-1 mutants with the WASP-family verprolin homologous protein complex-related gene depletions and corroborates the implication of RSF-1 in the regulation of actin cytoskeleton. In rsf-1 mutants, the structures of muscle actin are preserved, but the swimming ability is impaired. Although we could not detect the direct physical interaction of LET-60 with RSF-1, rsf-1 mutants suppress the multivulva phenotype of the active let-60 mutants, suggesting that rsf-1 genetically interacts with the Ras signaling., (Copyright © 2012 Elsevier Inc. All rights reserved.)

In immuno-light and -electron microscopy, brain-type fatty acid binding protein (B-FABP) is localized in the sustentacular cells enclosing the chromaffin cells in the adrenal medulla. This represents another new feature commonly shared by the sustentacular cells and ganglionic satellite cells, the latter of which has already been reported to localize this molecule, and suggests a common feature in lipid metabolism shared by the two cells enclosing peripheral neurons and paraneurons. On the other hand, epidermal-type fatty acid binding protein (E-FABP) is localized in two discrete cells in the adrenal gland: the one is a subpopulation of intra-adrenal macrophages which are intensely immunoreactive for F4/80, a marker of macrophages, and are rich in pleomorphic lysosomes. Because of their direct apposition to adjacent cortical endocrine cells and medullary chromaffin cells, the macrophages may be involved not only in phagocytosis of degenerating adrenal cells but also in exertion of some yet unknown effects on the endocrine function of the cortical and medullary cells via humoral factors such as cytokines which have recently been known to be secreted by macrophages. The other is a population of cells having scanty perikaryal cytoplasm poor in organneles and several thinny extended processes in the cortex and exhibiting weak immunoreactivity for E-FABP. The possible natures of these cells immunoreactive for E-FABP are discussed in view of a subpopulation of endothelial cells or the dendritic cells of antigen-presenting property.

Dendritic cells in the splenic white pulp of mice were intensely immunoreactive for epidermal-type fatty acid binding protein (E-FABP). This specific immunostaining revealed a clear difference in morphology between the dendritic cells in the periarterial lymphoid sheath (PALS) and follicular dendritic cells in the follicles in terms of cell sizes and process branching. No immunoreactivity was detected in dendritic cells in the marginal zones and the red pulp, although endothelial cells of almost all capillaries in the red pulp were immunoreactive for E-FABP. After peritoneal injection of lipopolysaccharide, the immunoreactive cells in PALS progressively enlarged and became rounded in shape with a peak in size at 24 h postinjection and they eventually resumed the dendritic form at 48 h postinjection. Within each of the enlarged immunoreactive cell perikarya were included small immunonegative apoptotic cells, presumptive lymphocytes. Taken together, E-FABP is useful as a marker for dendritic cells in the splenic white pulp, and may be involved through combination with fatty acids in antigen presentation and retention as well as in cytokine production.

Brain-type fatty acid-binding protein (B-FABP) was localized in Kupffer cells of liver of postnatal day 10 (P10) and older mice in immunolight and electron microscopy as well as by in situ hybridization histochemistry. The immunoreaction products were localized in the cytoplasmic matrix but not within the nucleus. After peritoneal injection of lipopolysaccharide (LPS), the immunoreaction for B-FABP decreased markedly in Kupffer cells at 1 h postinjection and thereafter gradually recovered to the preinjection level by 24 h postinjection, although no decrease in the mRNA expression was detected in Northern blotting throughout the course after the injection. The specific localization of B-FABP, but not the other FABPs, in Kupffer cells, and its rapid decrease after LPS injection suggest the intimate involvement of B-FABP in Kupffer cells in the inflammatory reaction, probably through mediation of n-3 polyunsaturated fatty acids, which are strong binders of B-FABP.

The immunoreactivity for epidermal-type fatty acid binding protein of epidermis type (E-FABP) was selectively localized in the epithelial cells of both cortex and medulla of mouse thymus. The cortical epithelial cytoreticulum was clearly visible with the intense immunoreactivity and the immunoreactive cytoreticulum extended intricately throughout the thymic cortex to enclose thymocytes. In the thymic medulla, the immunoreactivity was variable in intensity among the epithelial cells and there was a tendency that epithelial cells containing more numerous tonofilament bundles were less immunoreactive. Considering the possibility that FABPs function as intracellular carriers for unsaturated long chain fatty acids, the present finding suggests that E-FABP in the thymic epithelial cells, especially the cortical ones because of their extensive location, are intimately involved in the metabolic processes of fatty acids including production of bioactive substances, such as prostaglandin and leukotriene, which are known to exert some regulation of thymic immune responses.

Almost all alveolar macrophages in the mouse lung were strongly immunoreactive for epidermal-type fatty acid binding protein. At the electron microscope level, the immunoreactive material was localized diffusely in the cytoplasm but not within the nucleus. A certain number of alveolar type II epithelial cells were also immunoreactive for the protein with variable immunointensity, while a substantial number of the type II cells were immunonegative. No immunoreactive interstitial fibroblasts were encountered. Based on the present findings, possible roles of epidermal-type fatty acid binding protein in the host-defence mechanism played by alveolar macrophages are suggested.