Boning up on autophagy

From an evolutionary perspective, the major function of bone is to provide stable sites for muscle attachment and affording protection of vital organs, especially the heart and lungs (ribs) and spinal cord (vertebrae and intervertebral discs). However, bone has a considerable number of other functions: serving as a store for mineral ions, providing a site for blood cell synthesis and participating in a complex system-wide endocrine system. Not surprisingly, bone and cartilage cell homeostasis is tightly controlled, as is the maintenance of tissue structure and mass. While a great deal of new information is accruing concerning skeletal cell homeostasis, one relatively new observation is that the cells of bone (osteoclasts osteoblasts and osteocytes) and cartilage (chondrocytes) exhibit autophagy. The focus of this review is to examine the significance of this process in terms of the functional demands of the skeleton in health and during growth and to provide evidence that dysregulation of the autophagic response is involved in the pathogenesis of diseases of bone (Paget disease of bone) and cartilage (osteoarthritis and the mucopolysaccharidoses). Delineation of molecular changes in the autophagic process is uncovering new approaches for the treatment of diseases that affect the axial and appendicular skeleton.     

Eph/ephrin signaling in cancer

The Eph receptor tyrosine kinases family and their membrane bound ligands, the ephrins, represents a complex signaling network of cell communication for cell sorting during tissue patterning in development and in the normal physiology and homeostasis of adult tissues. This molecular family has adapted to evolving tissue complexity in multicellular organisms through the emergence of more members and complex mechanisms of expression and signaling that result in the fine-tuning of cell positioning. Since their initial identification from an erythropoietin producing hepatocellular (Eph) carcinoma cell line in 1987, Eph/ephrin signaling has been a matter of intensive investigation for their plausible role in cancer. Similarly to their context dependent modus operandi in normal tissues, Eph/ephrin signaling in cancer is an intricate and puzzling network of events that tumors “manage” to their benefit in multiple aspects like cell adhesion to substrate, migration, invasion or growth.     

Boning up on autophagy: The role of autophagy in skeletal biology

From an evolutionary perspective, the major function of bone is to provide stable sites for muscle attachment and affording protection of vital organs, especially the heart and lungs (ribs) and spinal cord (vertebrae and intervertebral discs). However, bone has a considerable number of other functions: serving as a store for mineral ions, providing a site for blood cell synthesis and participating in a complex system-wide endocrine system. Not surprisingly, bone and cartilage cell homeostasis is tightly controlled, as is the maintenance of tissue structure and mass. While a great deal of new information is accruing concerning skeletal cell homeostasis, one relatively new observation is that the cells of bone (osteoclasts osteoblasts and osteocytes) and cartilage (chondrocytes) exhibit autophagy. The focus of this review is to examine the significance of this process in terms of the functional demands of the skeleton in health and during growth and to provide evidence that dysregulation of the autophagic response is involved in the pathogenesis of diseases of bone (Paget disease of bone) and cartilage (osteoarthritis and the mucopolysaccharidoses). Delineation of molecular changes in the autophagic process is uncovering new approaches for the treatment of diseases that affect the axial and appendicular skeleton.     

Eph/ephrin recognition and the role of Eph/ephrin clusters in signaling initiation

The Eph receptors and their ephrin ligands play crucial roles in a large number of cell–cell interaction events, including those associated with axon pathfinding, neuronal cell migration and vasculogenesis. They are also involved in the patterning of most tissues and overall cell positioning in the development of the vertebrate body plan. The Eph/ephrin signaling system manifests several unique features that differentiate it from other receptor tyrosine kinases, including initiation of bi-directional signaling cascades and the existence of ligand and receptor subclasses displaying promiscuous intra-subclass interactions, but very rare inter-subclass interactions. In this review we briefly discuss these features and focus on recent studies of the unique and expansive high-affinity Eph/ephrin assemblies that form at the sites of cell–cell contact and are required for Eph signaling initiation. This article is part of a Special Issue entitled: Emerging recognition and activation mechanisms of receptor tyrosine kinases.     

Eph/ephrin signaling in epidermal differentiation and disease

Eph receptor tyrosine kinases mediate cell-cell communication by interacting with ephrin ligands residing on adjacent cell surfaces. In doing so, these juxtamembrane signaling complexes provide important contextual information about the cellular microenvironment that helps orchestrate tissue morphogenesis and maintain homeostasis. Eph/ephrin signaling has been implicated in various aspects of mammalian skin physiology, with several members of this large family of receptor tyrosine kinases and their ligands present in the epidermis, hair follicles, sebaceous glands, and underlying dermis. This review focuses on the emerging role of Eph receptors and ephrins in epidermal keratinocytes where they can modulate proliferation, migration, differentiation, and death. The activation of Eph receptors by ephrins at sites of cell-cell contact also appears to play a key role in the maturation of intercellular junctional complexes as keratinocytes move out of the basal layer and differentiate in the suprabasal layers of this stratified, squamous epithelium. Furthermore, alterations in the epidermal Eph/ephrin axis have been associated with cutaneous malignancy, wound healing defects and inflammatory skin conditions. These collective observations suggest that the Eph/ephrin cell-cell communication pathway may be amenable to therapeutic intervention for the purpose of restoring epidermal tissue homeostasis and integrity in dermatological disorders.     

Eph/ephrin signaling in epithelial development and homeostasis

Eph receptors and ephrin ligands are widely expressed during embryonic development with well-defined functions in directing neuronal and vascular network formation. Over the last decade, evidence has mounted that Ephs and ephrins are also actively involved in prenatal and postnatal development of epithelial tissues. Their functions beyond developmental settings are starting to be recognized as well. The diverse functions of Eph/ephrin are largely related to the complementary expression pattern of the Eph receptors and corresponding ephrin ligands that are expressed in adjacent compartments, although overlapping expression pattern also exists in epithelial tissue. The interconnection between Ephs or ephrins and classical cell junctional molecules suggests they may function coordinately in maintaining epithelial structural integrity and homeostasis. This review will highlight cellular and molecular evidence in current literature that support a role of Eph/ephrin systems in regulating epithelial cell development and physiology.     

Boning up on glypicans—opportunities for new insights into bone biology

Bone formation is remarkable for the convergence in the activity of four major signalling pathways, the bone morphogenetic protein (BMP), fibroblast growth factor (FGF), hedgehog (HH) and wingless‐integrated (WNT) pathways. These pathways cooperate in morphogenetic, proliferative and differentiative processes that underpin the development, growth and repair of skeletal structures. They are regulated by pathway‐specific modulators and by another class of molecules, the glypicans. Glypicans are proteoglycans located on the cell surface, where they act as coreceptors to promote or inhibit signalling by ligands of the BMP, FGF, HH and WNT pathways, through protein–protein and protein–carbohydrate interactions. In this review, we discuss glypican structure, expression and function in the context of bone development and growth, with emphasis on the long bone growth plate where five of the six glypicans are expressed in overlapping patterns in the chondrogenic zone. Analyses of gene knockout models and the human conditions of Simpson–Golabi–Behmel syndrome and omodysplasia, which arise from mutations in glypican 3 (GPC3) and GPC6, respectively, highlight both subtle and striking effects of glypicans on bone growth. We draw attention to challenges and areas of opportunity, where the actions of glypicans on BMP, FGF, HH and WNT signalling might be profitably studied to help illuminate the complex interplay of signalling that drives bone growth. Copyright © 2013 John Wiley & Sons, Ltd.     

The role of proteases in regulating Eph/ephrin signaling

Proteases regulate a myriad of cell functions, both in normal and disease states. In addition to protein turnover, they regulate a range of signaling processes, including those mediated by Eph receptors and their ephrin ligands. A variety of proteases is reported to directly cleave Ephs and/or ephrins under different conditions, to promote receptor and/or ligand shedding, and regulate receptor/ligand internalisation and signaling. They also cleave other adhesion proteins in response to Eph-ephrin interactions, to indirectly facilitate Eph-mediated functions. Proteases thus contribute to Eph/ephrin mediated changes in cell-cell and cell-matrix interactions, in cell morphology and in cell migration and invasion, in a manner which appears to be tightly regulated by, and co-ordinated with, Eph signaling. This review summarizes the current literature describing the function and regulation of protease activities during Eph/ephrin-mediated cell signaling.     

Regulation of cell differentiation by Eph receptor and ephrin signaling

There is increasing evidence that in addition to having major roles in morphogenesis, in some tissues Eph receptor and ephrin signaling regulates the differentiation of cells. In one mode of deployment, cell contact dependent Eph-ephrin activation induces a distinct fate of cells at the interface of their expression domains, for example in early ascidian embryos and in the vertebrate hindbrain. In another mode, overlapping Eph receptor and ephrin expression underlies activation within a cell population, which promotes or inhibits cell differentiation in bone remodelling, neural progenitors and keratinocytes. Eph-ephrin activation also contributes to formation of the appropriate number of progenitor cells by increasing or decreasing cell proliferation. These multiple roles of Eph receptor and ephrin signaling may enable a coupling between morphogenesis and the differentiation and proliferation of cells.     

Eph and ephrin signaling in the formation of topographic maps

The axonal connections between the retina and its midbrain target, the superior colliculus (SC), is mapped topographically, such that the spatial relationships of cell bodies in the retina are maintained when terminating in the SC. Topographic map development uses a Cartesian mapping system such that each axis of the retina is mapped independently. Along the nasal-temporal mapping axis, EphAs and ephrin-As, are graded molecular cues required for topographic mapping while the dorsal-ventral axis is mapped in part via EphB and ephrin-Bs. Because both Ephs and ephrins are cell surface molecules they can signal in the forward and reverse directions. Eph/ephrin signaling leads to changes in cytoskeletal dynamics that lead to actin depolymerization and endocytosis guiding axons via attraction and repulsion.     

The role of proteases in regulating Eph/ephrin signaling

Proteases regulate a myriad of cell functions, both in normal and disease states. In addition to protein turnover, they regulate a range of signaling processes, including those mediated by Eph receptors and their ephrin ligands. A variety of proteases is reported to directly cleave Ephs and/or ephrins under different conditions, to promote receptor and/or ligand shedding, and regulate receptor/ligand internalisation and signaling. They also cleave other adhesion proteins in response to Eph-ephrin interactions, to indirectly facilitate Eph-mediated functions. Proteases thus contribute to Eph/ephrin mediated changes in cell-cell and cell-matrix interactions, in cell morphology and in cell migration and invasion, in a manner which appears to be tightly regulated by, and co-ordinated with, Eph signaling. This review summarizes the current literature describing the function and regulation of protease activities during Eph/ephrin-mediated cell signaling.     

Regulation of cell differentiation by Eph receptor and ephrin signaling

There is increasing evidence that in addition to having major roles in morphogenesis, in some tissues Eph receptor and ephrin signaling regulates the differentiation of cells. In one mode of deployment, cell contact dependent Eph-ephrin activation induces a distinct fate of cells at the interface of their expression domains, for example in early ascidian embryos and in the vertebrate hindbrain. In another mode, overlapping Eph receptor and ephrin expression underlies activation within a cell population, which promotes or inhibits cell differentiation in bone remodelling, neural progenitors and keratinocytes. Eph-ephrin activation also contributes to formation of the appropriate number of progenitor cells by increasing or decreasing cell proliferation. These multiple roles of Eph receptor and ephrin signaling may enable a coupling between morphogenesis and the differentiation and proliferation of cells.     

Eph and ephrin signaling: lessons learned from spinal motor neurons

In nervous system assembly, Eph/ephrin signaling mediates many axon guidance events that shape the formation of precise neuronal connections. However, due to the complexity of interactions between Ephs and ephrins, the molecular logic of their action is still being unraveled. Considerable advances have been made by studying the innervation of the limb by spinal motor neurons, a series of events governed by Eph/ephrin signaling. Here, we discuss the contributions of different Eph/ephrin modes of interaction, downstream signaling and electrical activity, and how these systems may interact both with each other and with other guidance molecules in limb muscle innervation. This simple model system has emerged as a very powerful tool to study this set of molecules, and will continue to be so by virtue of its simplicity, accessibility and the wealth of pioneering cellular studies.     

The multifaceted roles of Eph/ephrin signaling in breast cancer

Eph receptors and their membrane-bound ligands are intimately involved in the control of morphogenic processes during embryonic development and adult tissue homeostasis. By their ability to orchestrate cell migration, pattern formation and tissue integrity they are also prone to be involved in carcinogenic growth. In this review we concentrate on their involvement in the normal and carcinogenic development of the breast. In this context we summarize their multi-faceted functions as tumor suppressors, tumor promoters, angiogenic inducers and regulators of stem cell homeostasis.     

Eph/ephrin signaling in morphogenesis, neural development and plasticity

Ephrins are cell-surface-tethered ligands for Eph receptors, the largest family of receptor tyrosine kinases. During development, the Eph/ephrin cell communication system appears to influence cell behavior such as attraction/repulsion, adhesion/de-adhesion and migration, thereby influencing cell fate, morphogenesis and organogenesis. During adulthood, the Eph/ephrin system continues to play roles in tissue plasticity, for example in shaping dendritic spines during neuronal plasticity. Mechanistically, Eph-ephrin repulsive behavior appears to require ligand-receptor internalization and signaling to Rho GTPases.     

The multifaceted roles of Eph/ephrin signaling in breast cancer

Eph receptors and their membrane-bound ligands are intimately involved in the control of morphogenic processes during embryonic development and adult tissue homeostasis. By their ability to orchestrate cell migration, pattern formation and tissue integrity they are also prone to be involved in carcinogenic growth. In this review we concentrate on their involvement in the normal and carcinogenic development of the breast. In this context we summarize their multi-faceted functions as tumor suppressors, tumor promoters, angiogenic inducers and regulators of stem cell homeostasis.