Adenomatous Polyposis Coli (APC) in cell migration

Adenomatous Polyposis Coli (APC) protein is mostly known as a tumor suppressor that regulates Wnt signaling, but is also an important cytoskeletal protein. Mutations in the APC gene are linked to colorectal cancer and various neurological disorders and intellectual disabilities. Cytoskeletal functions of APC appear to have significant contributions to both types of these disorders. As a cytoskeletal protein, APC can regulate both actin and microtubule cytoskeletons, which together form the main machinery for cell migration. As APC is a multifunctional protein with numerous interaction partners, the complete picture of how APC regulates cell motility is still unavailable. However, some molecular mechanisms begin to emerge. Here, we review available information about roles of APC in cell migration and propose a model explaining how microtubules, using APC as an intermediate, can initiate leading edge protrusion in response to external signals by stimulating Arp2/3 complex-dependent nucleation of branched actin filament networks via a series of intermediate events.     

Prey capture by Luciocephalus pulcher: implications for models of jaw protrusion in teleost fishes

Synopsis Luciocephalus pulcher possesses one of the most protrusible jaws known among teleosts, the premaxillae extending anteriorly a distance of 33% of the head length during feeding. Jaw bone movement during feeding proceeds according to a stereotypical pattern and resembles that of other teleosts except for extreme cranial elevation and premaxillary protrusion. Anatomical specializations associated with cranial elevation include: a highly modified first vertebra with a separate neural spine, articular fossae on the posterior aspect, greatly enlarged zygapophyses on the second vertebra with complex articular condyles, and highly pinnate multi-layered epaxial musculature with multiple tendinous insertions on the skull. Luciocephalus, despite the extreme jaw protrusion, does not use suction during prey capture: rather, the prey is captured by a rapid lunge (peak velocity of about 150 cm per sec) and is surrounded by the open mouth. Previous hypotheses of the function of upper jaw protrusion are reviewed in relation to jaw movements inLuciocephalus. Protrusion is not obligatorily linked with suction feeding; behavioral aspects of the feeding process limit the possible range of biological roles of a given morphological specialization, and make prediction of role from structure risky.     

Advances in the Study of Feeding Behaviors, Mechanisms, and Mechanics of Sharks

Sharks as a group have a long history as highly successful predatory fishes. Although, the number of recent studies on their diet, feeding behavior, feeding mechanism, and mechanics have increased, many areas still require additional investigation. Dietary studies of sharks are generally more abundant than those on feeding activity patterns, and most of the studies are confined to relatively few species, many being carcharhiniform sharks. These studies reveal that sharks are generally asynchronous opportunistic feeders on the most abundant prey item, which are primarily other fishes. Studies of natural feeding behavior are few and many observations of feeding behavior are based on anecdotal reports. To capture their prey sharks either ram, suction, bite, filter, or use a combination of these behaviors. Foraging may be solitary or aggregate, and while cooperative foraging has been hypothesized it has not been conclusively demonstrated. Studies on the anatomy of the feeding mechanism are abundant and thorough, and far exceed the number of functional studies. Many of these studies have investigated the functional role of morphological features such as the protrusible upper jaw, but only recently have we begun to interpret the mechanics of the feeding apparatus and how it affects feeding behavior. Teeth are represented in the fossil record and are readily available in extant sharks. Therefore much is known about their morphology but again functional studies are primarily theoretical and await experimental analysis. Recent mechanistic approaches to the study of prey capture have revealed that kinematic and motor patterns are conserved in many species and that the ability to modulate feeding behavior varies greatly among taxa. In addition, the relationship of jaw suspension to feeding behavior is not as clear as was once believed, and contrary to previous interpretations upper jaw protrusibility appears to be related to the morphology of the upper jaw-chondrocranial articulation rather than the type of jaw suspension. Finally, we propose a set of specific hypotheses including: (1) The functional specialization for suction feeding hypothesis that morphological and functional specialization for suction feeding has repeatedly arisen in numerous elasmobranch lineages, (2) The aquatic suction feeding functional convergence hypothesis that similar hydrodynamic constraints in bony fishes and sharks result in convergent morphological and functional specializations for suction feeding in both groups, (3) The feeding modulation hypothesis that suction capture events in sharks are more stereotyped and therefore less modulated compared to ram and bite capture events, and (4) The independence of jaw suspension and feeding behavior hypothesis whereby the traditional categorization of jaw suspension types in sharks is not a good predictor of jaw mobility and prey capture behavior. Together with a set of questions these hypotheses help to guide future research on the feeding biology of sharks.     

Characterization of local geometry of protein surfaces with the visibility criterion

Experimentally determined protein tertiary structures are rapidly accumulating in a database, partly due to the structural genomics projects. Included are proteins of unknown function, whose function has not been investigated by experiments and was not able to be predicted by conventional sequence-based search. Those uncharacterized protein structures highlight the urgent need of computational methods for annotating proteins from tertiary structures, which include function annotation methods through characterizing protein local surfaces. Toward structure-based protein annotation, we have developed VisGrid algorithm that uses the visibility criterion to characterize local geometric features of protein surfaces. Unlike existing methods, which only concerns identifying pockets that could be potential ligand-binding sites in proteins, VisGrid is also aimed to identify large protrusions, hollows, and flat regions, which can characterize geometric features of a protein structure. The visibility used in VisGrid is defined as the fraction of visible directions from a target position on a protein surface. A pocket or a hollow is recognized as a cluster of positions with a small visibility. A large protrusion in a protein structure is recognized as a pocket in the negative image of the structure. VisGrid correctly identified 95.0% of ligand-binding sites as one of the three largest pockets in 5616 benchmark proteins. To examine how natural flexibility of proteins affects pocket identification, VisGrid was tested on distorted structures by molecular dynamics simulation. Sensitivity decreased approximately 20% for structures of a root mean square deviation of 2.0 A to the original crystal structure, but specificity was not much affected. Because of its intuitiveness and simplicity, the visibility criterion will lay the foundation for characterization and function annotation of local shape of proteins.     

Direct visualization of epithelial microvilli biogenesis

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HuBMSC-MCP, a novel member of mitochondrial carrier superfamily, enhances dendritic cell endocytosis

A novel member of mitochondrial carrier superfamily has been identified from human bone marrow stromal cells (BMSC) and designated as human BMSC-derived mitochondrial carrier protein (HuBMSC-MCP). It encodes a 321 amino-acid protein with three tandem related domains of about 100 amino acids. Each domain contains two hydrophobic stretches, which are thought to span the membrane as alpha-helices. Distant relationship analysis indicates that the protein is highly conserved between species from Caenorhabditis elegans to human. HuBMSC-MCP gene is mapped to chromosome 11p11. HuBMSC-MCP mRNA expression is detectable in various human tissues and cell lines. By confocal imaging, HuBMSC-MCP is localized to mitochondria and also detected in the pseudopodial protrusion of human breast adenocarcinoma MCF-7 cells. When transfected into dendritic cells (DC), HuBMSC-MCP could enhance DCs endocytotic capacity. Thus, HuBMSC-MCP is a phylogenetically conserved and widely expressed mitochondrial carrier protein which perhaps associates with mitochondrial oxidative phosphorylation.     

Distinct Interaction Sites of Rac GTPase with WAVE Regulatory Complex Have Non-redundant Functions in Vivo

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Membrane protrusion powers clathrin-independent endocytosis of interleukin-2 receptor

Endocytosis controls many functions including nutrient uptake, cell division, migration and signal transduction. A clathrin- and caveolin-independent endocytosis pathway is used by important physiological cargos, including interleukin-2 receptors (IL-2R). However, this process lacks morphological and dynamic data. Our electron microscopy (EM) and tomography studies reveal that IL-2R-pits and vesicles are initiated at the base of protrusions. We identify the WAVE complex as a specific endocytic actor. The WAVE complex interacts with IL-2R, via a WAVE-interacting receptor sequence (WIRS) present in the receptor polypeptide, and allows for receptor clustering close to membrane protrusions. In addition, using total internal reflection fluorescent microscopy (TIRF) and automated analysis we demonstrate that two timely distinct bursts of actin polymerization are required during IL-2R uptake, promoted first by the WAVE complex and then by N-WASP. Finally, our data reveal that dynamin acts as a transition controller for the recruitment of Arp2/3 activators required for IL-2R endocytosis. Altogether, our work identifies the spatio-temporal specific role of factors initiating clathrin-independent endocytosis by a unique mechanism that does not depend on the deformation of a flat membrane, but rather on that of membrane protrusions.