Distinct endocytic pathways regulate TGF-β receptor signalling and turnover

Guglielmo, Gianni M. Di; Roy, Christine Le; Goodfellow, Anne F; Wrana, Jeffrey L.

doi:10.1038/ncb975

Cited by 1,064 publications

(1,273 citation statements)

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“…Additionally, caveolae can rapidly modulate signaling through an endocytotic mechanism by which the caveolae internalize receptors or other signaling components so that they are non-functional. These endocytosed structures can remain near the membrane surface so that they can be made available for signaling by reintroduction to the membrane surface facilitated by the caveolae [46,118,119].…”

Section: Discussionmentioning

confidence: 99%

Caveolin proteins and estrogen signaling in the brain

Luoma

Boulware

Mermelstein

2008

Molecular and Cellular Endocrinology

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Best described outside the nervous system, caveolins are structural proteins that form caveolae, functional microdomains at the plasma membrane that cluster related signaling molecules. Caveolin associated proteins include G protein coupled receptors and G proteins, receptor tyrosine kinases, as well as protein kinases, ion channels and various other signaling enzymes. Not surprisingly, a wide array of biological disorders are thought to be rooted in caveolin dysfunction. In addition, caveolins also traffic and cluster estrogen receptors to caveolae. Interactions between the estrogen receptors ERα and ERβ with caveolins appear critical in many non-neuronal cell types, e.g. disruption of normal function may underlie many forms of breast cancer. Recent findings suggest caveolins may also play an essential role in membrane estrogen receptor function in the nervous system. Not only are they expressed in neurons and glia, but different caveolin isoforms also appear necessary to generate distinct functional signaling complexes. With membrane estrogen receptors responsible for the efficient activation of a multitude of intracellular signaling pathways, which in turn influence a wide variety of nervous system functions, caveolin proteins are poised to act as the central coordinators of these processes.

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Section: Discussionmentioning

confidence: 99%

Caveolin proteins and estrogen signaling in the brain

Luoma

Boulware

Mermelstein

2008

Molecular and Cellular Endocrinology

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“…Cell surface ActRII was then labeled with fluorescent anti-Myc antibodies (as in Di Guglielmo et al, 2003). After labeling, receptor internalization was initiated by shifting the cells for 1 hr to 23°C.…”

Section: Internalization Testmentioning

confidence: 99%

Two‐dimensional morphogen gradient in Xenopus: Boundary formation and real‐time transduction response

Kinoshita

Jullien

Gurdon

2006

Developmental Dynamics

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Morphogen gradients play an important role in pattern formation in embryo. However, the interpretation of position in a morphogen gradient is not well understood. Because it is hard to analyze morphogen gradients especially in opaque embryos such as those of Xenopus, it is necessary to fix and section the embryo, thereby eliminating the possibility of real-time observation, and making more difficult the interpretation of events that take place in three dimensions. We describe here a two-dimensional preparation of cells from a Xenopus blastula animal cap, in which an activin concentration gradient appears to be formed and interpreted at the same rate and in the same way as in normal embryos. We use two-dimensional preparations of this kind to contribute the following new information about gradient formation and interpretation in embryo. We determine the dynamics of formation of an activin activity gradient in real time. We demonstrate that this gradient is established by diffusion of activin through intercellular space and does not require internalization of receptor or ligand. We also show that the generation of a boundary of gene expression depends on the interpretation, rather than a change of composition, of the concentration gradient. Developmental Dynamics 235:3189 -3198, 2006.

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“…In this model, the RGM-BMP complex (potentially together with the BMP type II receptor) might be targeted into endosomes, which are enriched with BMP type I receptors [20]. The lower pH of the endosomal environment might then lead to dissociation of the RGM-BMP complex and replacement by the BMP type I receptor, leading to potentiation of SMAD signaling provided by the endosomal environment compared with the cell surface [20,21]. However, further work will be required to test this model, for example demonstrating the involvement of RGMs in BMP ligand endocytosis and showing that the endosome functions as a platform for BMP signaling.…”

Section: Structural Insight Into Ligand-receptor Interactionsmentioning

confidence: 99%

Section: Structural Insight Into Ligand-receptor Interactionsmentioning

confidence: 99%

“…However, localization of the signaling machinery in close vicinity to the nucleus is a favorable way of activating target gene transcription. Such a mechanism has been suggested for other extracellular signaling systems, including the epidermal growth factor and transforming growth factor signaling pathways [21][22][23].Much evidence suggests that the Neogenin and BMP signaling pathways are functionally linked, most likely through the actions of RGMs [9,[24][25][26][27]. The most compelling evidence is the iron overload observed in the livers of mice in which the gene encoding Neogenin (NEO) has been knocked out [28].…”

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confidence: 99%

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RGMs: Structural Insights, Molecular Regulation, and Downstream Signaling

Siebold

Yamashita

Monnier

et al. 2017

Trends in Cell Biology

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Although originally discovered as neuronal growth cone-collapsing factors, repulsive guidance molecules (RGMs) are now known as key players in many fundamental processes, such as cell migration, differentiation, iron homeostasis, and apoptosis, during the development and homeostasis of many tissues and organs, including the nervous, skeletal, and immune systems. Furthermore, three RGMs (RGMa, RGMb/DRAGON, and RGMc/hemojuvelin) have been linked to the pathogenesis of various disorders ranging from multiple sclerosis (MS) to cancer and juvenile hemochromatosis (JHH). While the molecular details of these (patho) biological effects and signaling modes have long remained unknown, recent studies unveil several exciting and novel aspects of RGM processing, ligand-receptor interactions, and downstream signaling. In this review, we highlight recent advances in the mechanisms-of-action and function of RGM proteins. RGMs: A Small Gene Family with Widespread EffectsGuidance molecules, initially observed to direct growing axons during embryogenesis [1], also have crucial roles in the morphogenesis and homeostasis of non-neuronal tissues by controlling a plethora of cellular processes, ranging from cell division and migration to differentiation and death. Figure 1A). Each RGM displays tissuespecific expression, is subjected to distinct biosynthetic and processing steps, and has not only unique, but also shared biological functions [2]. RGMs bind the type 1 transmembrane protein Neogenin ( Figure 1A) and many of the reported biological effects of RGMs rely on Neogenin receptor functions, such as axon guidance or neuronal survival [3,4]. RGMs also serve as co-receptors for bone morphogenetic proteins (BMPs) ( Figure 1A) to regulate iron metabolism, skeletal development [5-10] and axon regeneration [11]. In addition to these physiological roles, and as discussed below, RGMs have been implicated in various diseases and are considered to be promising targets in the treatment of MS, spinal cord injury, stroke, anemia, and inflammation [5,[11][12][13][14][15].Although the molecular mechanisms underlying the biological effects and signaling modes of RGMs have long remained unknown, recent work has unveiled several exciting and novel aspects of RGM processing, ligand-receptor interactions, and downstream signaling. These insights include high-resolution structural data of binary or tertiary protein complexes, the unique processing of RGMs into protein fragments with distinct functions, and the identification of a novel molecular mechanism to control ligand-induced ectodomain shedding of Neogenin. In this review, we discuss recent highlights in RGM research, from novel structural data to previously unexplored signaling mechanisms and cellular functions. Structural Insight into Ligand-Receptor InteractionsFor many years, RGMs posed a molecular puzzle because of a general lack of structural homologies to any known protein fold. Recent studies have shed light on their 3D structure and identified two ordered and disulfide-stabiliz...

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Distinct endocytic pathways regulate TGF-β receptor signalling and turnover

Cited by 1,064 publications

References 50 publications

Caveolin proteins and estrogen signaling in the brain

Caveolin proteins and estrogen signaling in the brain

Two‐dimensional morphogen gradient in Xenopus: Boundary formation and real‐time transduction response

RGMs: Structural Insights, Molecular Regulation, and Downstream Signaling

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