scholarly journals Dispatching plasma membrane cholesterol and Sonic Hedgehog dispatch: two sides of the same coin?

2021 ◽  
Author(s):  
Kristina Ehring ◽  
Kay Grobe
Keyword(s):  
Plasma Membrane ◽  
Cell Fate ◽  
Signal Sequence ◽  
Target Cells ◽  
Cell Fate Decisions ◽  
Open Questions ◽  
New Findings ◽  
Resistance Nodulation Division ◽  
Rnd Transporter ◽  
Niemann Pick

Vertebrate and invertebrate Hedgehog (Hh) morphogens signal over short and long distances to direct cell fate decisions during development and to maintain tissue homeostasis after birth. One of the most important questions in Hh biology is how such Hh signaling to distant target cells is achieved, because all Hh proteins are secreted as dually lipidated proteins that firmly tether to the outer plasma membrane leaflet of their producing cells. There, Hhs multimerize into light microscopically visible storage platforms that recruit factors required for their regulated release. One such recruited release factor is the soluble glycoprotein Scube2 (Signal sequence, cubulin domain, epidermal-growth-factor-like protein 2), and maximal Scube2 function requires concomitant activity of the resistance-nodulation-division (RND) transporter Dispatched (Disp) at the plasma membrane of Hh-producing cells. Although recently published cryo-electron microscopy-derived structures suggest possible direct modes of Scube2/Disp-regulated Hh release, the mechanism of Disp-mediated Hh deployment is still not fully understood. In this review, we discuss suggested direct modes of Disp-dependent Hh deployment and relate them to the structural similarities between Disp and the related RND transporters Patched (Ptc) and Niemann-Pick type C protein 1. We then discuss open questions and perspectives that derive from these structural similarities, with particular focus on new findings that suggest shared small molecule transporter functions of Disp to deplete the plasma membrane of cholesterol and to modulate Hh release in an indirect manner.

scholarly journals Activation of the MAPK Module from Different Spatial Locations Generates Distinct System Outputs

2008 ◽  
Vol 19 (11) ◽  
pp. 4776-4784 ◽  
Author(s):  
Kerry Inder ◽  
Angus Harding ◽  
Sarah J. Plowman ◽  
Mark R. Philips ◽  
Robert G. Parton ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Cell Fate ◽  
Mapk Pathway ◽  
Cell Fate Decisions ◽  
Raf Kinase ◽  
System Output ◽  
Multiple Cell ◽  
Spatial Locations ◽  
Distinct Membrane ◽  
Striking Contrast

The Ras/Raf/MEK/ERK (MAPK) pathway directs multiple cell fate decisions within a single cell. How different system outputs are generated is unknown. Here we explore whether activating the MAPK module from different membrane environments can rewire system output. We identify two classes of nanoscale environment within the plasma membrane. The first, which corresponds to nanoclusters occupied by GTP-loaded H-, N- or K-Ras, supports Raf activation and amplifies low Raf kinase input to generate a digital ERKpp output. The second class, which corresponds to nanoclusters occupied by GDP-loaded Ras, cannot activate Raf and therefore does not activate the MAPK module, illustrating how lateral segregation on plasma membrane influences signal output. The MAPK module is activated at the Golgi, but in striking contrast to the plasma membrane, ERKpp output is analog. Different modes of Raf activation precisely correlate with these different ERKpp system outputs. Intriguingly, the Golgi contains two distinct membrane environments that generate ERKpp, but only one is competent to drive PC12 cell differentiation. The MAPK module is not activated from the ER. Taken together these data clearly demonstrate that the different nanoscale environments available to Ras generate distinct circuit configurations for the MAPK module, bestowing cells with a simple mechanism to generate multiple system outputs from a single cascade.

scholarly journals Conserved cholesterol-related activities of Dispatched drive Sonic hedgehog shedding from the cell membrane

2020 ◽  
Author(s):  
K. Ehring ◽  
D. Manikowski ◽  
J. Froese ◽  
J. Goretzko ◽  
P. Jakobs ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Sonic Hedgehog ◽  
Molecular Mechanisms ◽  
Tissue Homeostasis ◽  
Target Cells ◽  
Membrane Cholesterol ◽  
Ectodomain Shedding ◽  
Shh Pathway ◽  
Distant Target ◽  
Resistance Nodulation Division

SummaryThe Sonic hedgehog (Shh) pathway controls embryonic development and tissue homeostasis after birth. Long-lasting questions about this pathway are how dual-lipidated, firmly plasma membrane-associated Shh ligand is released from producing cells to signal to distant target cells, and how the resistance-nodulation-division transporter Dispatched (Disp) regulates this process. Here we show that Disp inactivation in Shh expressing cells specifically impairs proteolytic Shh release from its lipidated terminal peptides, a process called ectodomain shedding. Shh shedding from Disp-deficient cells was restored by pharmacological membrane cholesterol extraction and by overexpressed transgenic Disp or structurally related Patched (Ptc, a putative cholesterol transporter). These data suggest that Disp regulates physiological Shh function via controlled cell surface shedding and that molecular mechanisms shared by Disp and Ptc exercise such sheddase control.

scholarly journals Conserved cholesterol-related activities of dispatched drive Sonic hedgehog shedding from the cell membrane

2021 ◽  
Author(s):  
K. Ehring ◽  
D. Manikowski ◽  
J. Goretzko ◽  
J. Froese ◽  
F. Gude ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Sonic Hedgehog ◽  
Molecular Mechanisms ◽  
Tissue Homeostasis ◽  
Target Cells ◽  
Membrane Cholesterol ◽  
Ectodomain Shedding ◽  
Shh Pathway ◽  
Distant Target ◽  
Resistance Nodulation Division

The Sonic hedgehog (Shh) pathway controls embryonic development and tissue homeostasis after birth. Long-lasting questions about this pathway are how dual-lipidated, firmly plasma membrane-associated Shh ligand is released from producing cells to signal to distant target cells, and how the resistance-nodulation-division transporter Dispatched (Disp) regulates this process. Here we show that Disp inactivation in Shh expressing cells impairs proteolytic Shh release from its lipidated terminal peptides, a process called ectodomain shedding. We also show reduced cholesterol export from Disp-deficient cells, that these cells contain increased cholesterol amounts in the plasma membrane, and that Shh shedding from Disp-deficient cells is restored by pharmacological membrane cholesterol extraction and by overexpressed transgenic Disp or structurally related Patched (Ptc, a putative cholesterol transporter). These data suggest that Disp can regulate Shh function via controlled cell surface shedding and that membrane cholesterol-related molecular mechanisms shared by Disp and Ptc exercise such sheddase control.

scholarly journals The Conundrum of the Pericentral Hepatic Niche: WNT/-Catenin Signaling, Metabolic Zonation, and Many Open Questions

2020 ◽  
Vol 20 (2) ◽  
pp. 119-124
Author(s):  
Jan S. Tchorz
Keyword(s):  
Stem Cell ◽  
Cell Fate ◽  
Target Genes ◽  
Stem Cell Markers ◽  
High Turnover ◽  
Cell Fate Decisions ◽  
Cell Compartments ◽  
Hepatocyte Regeneration ◽  
Metabolic Zonation ◽  
Open Questions

WNT/-catenin signaling promotes stemness, proliferation, and cell fate decisions in various tissue stem cell compartments, which maintain organs with a high turnover of cells (e.g., skin, stomach, and gut). Thus, the -catenin target genes AXIN2 and LGR5 are widely considered as tissue stem cell markers. In contrast, AXIN2 and LGR5 are expressed in pericentral hepatocytes, which do not show overt proliferation during liver homeostasis. Given the low hepatocyte turnover, the liver does not require constant high rates of proliferation, whereas WNT/-catenin signaling is critical for metabolic zonation. Yet, WNT/-catenin pathway upregulation, including AXIN2 and LGR5 induction in hepatocytes throughout the liver, enables hepatocyte regeneration in response to various injuries. In this brief review, I discuss the role of WNT/-catenin signaling in controlling metabolic zonation and the conundrum around pericentral hepatocytes that have been proposed as liver stem cells.

scholarly journals Neoplastic Transformation by Notch Requires Nuclear Localization

2000 ◽  
Vol 20 (11) ◽  
pp. 3928-3941 ◽  
Author(s):  
Shawn Jeffries ◽  
Anthony J. Capobianco
Keyword(s):  
Plasma Membrane ◽  
Notch Signaling ◽  
Cell Fate ◽  
Mammalian Cells ◽  
Rat Kidney ◽  
Neoplastic Transformation ◽  
Notch Signaling Pathway ◽  
Proteolytic Processing ◽  
Cell Fate Decisions

ABSTRACT Notch proteins are plasma membrane-spanning receptors that mediate important cell fate decisions such as differentiation, proliferation, and apoptosis. The mechanism of Notch signaling remains poorly understood. However, it is clear that the Notch signaling pathway mediates its effects through intercellular contact between neighboring cells. The prevailing model for Notch signaling suggests that ligand, presented on a neighboring cell, triggers proteolytic processing of Notch. Following proteolysis, it is thought that the intracellular portion of Notch (Nic) translocates to the nucleus, where it is involved in regulating gene expression. There is considerable debate concerning where in the cell Notch functions and what proteins serve as effectors of the Notch signal. Several Notch genes have clearly been shown to be proto-oncogenes in mammalian cells. Activation of Notch proto-oncogenes has been associated with tumorigenesis in several human and other mammalian cancers. Transforming alleles of Notch direct the expression of truncated proteins that primarily consist of Nic and are not tethered to the plasma membrane. However, the mechanism by which Notch oncoproteins (generically termed here as Nic) induce neoplastic transformation is not known. Previously we demonstrated that N1ic and N2iccould transform E1A immortalized baby rat kidney cells (RKE) in vitro. We now report direct evidence that N1ic must accumulate in the nucleus to induce transformation of RKE cells. In addition, we define the minimal domain of N1ic required to induce transformation and present evidence that transformation of RKE cells by N1ic is likely to be through a CBF1-independent pathway.

scholarly journals Bazooka/Par3 cooperates with Sanpodo for the assembly of Notch signaling clusters following asymmetric division of Drosophila sensory organ precursor cells

2021 ◽  
Author(s):  
Elise Houssin ◽  
Mathieu Pinot ◽  
Karen Bellec ◽  
Roland Le Borgne
Keyword(s):  
Plasma Membrane ◽  
Notch Signaling ◽  
Cell Fate ◽  
Sensory Organ ◽  
Cell Fate Decisions ◽  
Daughter Cells ◽  
Delta Activity ◽  
Multiple Cell ◽  
Sensory Organ Precursor ◽  
Fate Decision

SummaryIn multiple cell lineages, Delta-Notch signaling regulates cell fate decisions owing to unidirectional signaling between daughter cells. In Drosophila pupal sensory organ lineage, Notch regulates pIIa/pIIb fate decision at cytokinesis. Notch and Delta that localize apically and basally at the pIIa-pIIb interface, are expressed at low levels and their residence time at the plasma membrane is in the order of the minute. How Delta can effectively interact with Notch to trigger signaling from a large plasma membrane remains poorly understood. Here, we report that the signaling interface possesses a unique apicobasal polarity with Par3/Bazooka localizing in the form of nano-clusters at the apical and basal level. Notch is preferentially targeted to the pIIa-pIIb interface where it co-clusters with Bazooka and the Notch cofactor Sanpodo. Clusters whose assembly relies on Bazooka and Sanpodo activities, are also positive for Neuralized, the E3 ligase required for Delta-activity. We propose that the nano-clusters act as snap buttons at the new pIIa-pIIb interface to allow efficient intra-lineage signaling.

scholarly journals Bazooka/Par3 cooperates with Sanpodo for the assembly of Notch clusters following asymmetric division of Drosophila sensory organ precursor cells

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Elise Houssin ◽  
Mathieu Pinot ◽  
Karen Bellec ◽  
Roland Le Borgne
Keyword(s):  
Plasma Membrane ◽  
Cell Fate ◽  
Sensory Organ ◽  
Membrane Area ◽  
Cell Fate Decisions ◽  
Daughter Cells ◽  
Delta Activity ◽  
Multiple Cell ◽  
Sensory Organ Precursor ◽  
Fate Decision

In multiple cell lineages, Delta-Notch signalling regulates cell fate decisions owing to unidirectional signalling between daughter cells. In Drosophila pupal sensory organ lineage, Notch regulates the intra-lineage pIIa/pIIb fate decision at cytokinesis. Notch and Delta that localise apically and basally at the pIIa-pIIb interface are expressed at low levels and their residence time at the plasma membrane is in the order of minutes. How Delta can effectively interact with Notch to trigger signalling from a large plasma membrane area remains poorly understood. Here, we report that the signalling interface possesses a unique apicobasal polarity with Par3/Bazooka localising in the form of nano-clusters at the apical and basal level. Notch is preferentially targeted to the pIIa-pIIb interface, where it co-clusters with Bazooka and its cofactor Sanpodo. Clusters whose assembly relies on Bazooka and Sanpodo activities are also positive for Neuralized, the E3 ligase required for Delta-activity. We propose that the nano-clusters act as snap buttons at the new pIIa-pIIb interface to allow efficient intra-lineage signalling.

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