---
# System prepended metadata

title: SHH signaling in astrocytes
tags: [shh]

---

---
title: SHH signaling in astrocytes
disqus: hackmd
---
:::success
> Documentation [name=MrDr.Staffan]
###### tags: `shh`

### Table of Contents
[TOC]
:::
[Top](#Table-of-Contents)

[See SHH Poster](https://documentcloud.adobe.com/gsuiteintegration/index.html?state=%7B%22ids%22%3A%5B%2219313bL6EYvzSGa6LAQLYXFum_Z4kEc3N%22%5D%2C%22action%22%3A%22open%22%2C%22userId%22%3A%22108270474537056948183%22%2C%22resourceKeys%22%3A%7B%7D%7D)

[See Gene list sheet (GO)](https://docs.google.com/spreadsheets/d/1spvXU2UWB29FwWB6Akg41uu-layOxZiF4lPzQut2U8g/edit#gid=1054564324)

Sonic hedgehog signaling in astrocytes
https://link.springer.com/article/10.1007/s00018-020-03668-8
Review 2021
Steven A. Hill, Marissa Fu & A. Denise R. Garcia


![](https://i.imgur.com/dec82bn.png)
[![image.png](https://hackmd.io/_uploads/BJhJbz_XT.png)](https://www.cell.com/trends/pharmacological-sciences/fulltext/S0165-6147(09)00069-8)
2009
SUFU Negative Regulator Of Hedgehog Signaling





# Sufu
SUFU Negative Regulator Of Hedgehog Signaling

Sequesters GLI1, GLI2 and GLI3 in the cytoplasm, this effect is overcome by binding of STK36 to both SUFU and a GLI protein (PubMed:10559945, 10564661, 10806483, 24217340).

Negative regulator of beta-catenin signaling

Negative regulator of beta-catenin signaling (By similarity). Regulates the formation of either the **repressor form (GLI3R)** or the **activator form (GLI3A)** of the full-length form of GLI3 (GLI3FL) (PubMed:24311597, 28965847). GLI3FL is complexed with SUFU in the cytoplasm and is maintained in a neutral state (PubMed:24311597, 28965847). Without the Hh signal, the SUFU-GLI3 complex is recruited to cilia, leading to the efficient processing of GLI3FL into GLI3R (PubMed:24311597, 28965847). 


[When no shh, there is Gli3 repression]

When Hh signaling is initiated, SUFU dissociates from GLI3FL and the latter translocates to the nucleus, where it is phosphorylated, destabilized, and converted to a transcriptional activator (GLI3A) (PubMed:24311597, 28965847).

# SHH acylation.

[2022 Hedgehog acyltransferase catalyzes a random sequential reaction and utilizes **multiple** fatty acyl-CoA substrates](https://www.jbc.org/article/S0021-9258(22)00865-1/fulltext)
![image](https://hackmd.io/_uploads/HJBjWm3OT.png)

[2021 Structure, mechanism, and inhibition of Hedgehog acyltransferase](https://www.cell.com/molecular-cell/fulltext/S1097-2765(21)00998-9)

Gas1 on receiving membrane. for binding of Shh to Ptch1 and subsequent signaling
Gas1 increase the signaling more when Palmitic, than octanoic. is coupled to SHH.

Hhat the enzyme transfering acyl to SHH.

![image](https://hackmd.io/_uploads/HJEyQXnua.png)





# Gli:s
"The GLI family consists of three members, GLI1, GLI2 and GLI3, all of which have a highly conserved zinc finger (ZF) domain that binds to the consensus GLI binding DNA sequence (GBS) GACCACCCA [2,3]"

canonical pathway, Hh ligands bind to cell surface Patched1 (PTCH1) leading to the release of Smoothened (SMO), a G-protein coupled receptor, which then triggers the downstream activation and nuclear targeting of GLI transcription factors [1,6]. By traveling through the membrane.


recent reports show that other signaling cascades, including RAS [7,8] and TGFβ [9], can also modulate GLI activity in cancer cells, thus demonstrating that GLI proteins are key effectors of multiple signaling pathways involved in normal and pathogenic cellular processes.

Eichberger et al. [13] demonstrated the existence of a subset of GLI1 and GLI2 co-regulated genes in keratinocytes

In this study, we demonstrate that GLI1 and GLI2 form a **protein complex** that plays a role in the regulation of gene expression in pancreatic cancer cells. We further show that both transcription factors regulate the expression of genes involved in modulation of cell growth and survival, including BCL2, MYCN and CCND1

[2020 GLI1/GLI2 functional interplay is required to control Hedgehog/GLI targets gene expression](https://portlandpress.com/biochemj/article-abstract/477/17/3131/226006/GLI1-GLI2-functional-interplay-is-required-to?redirectedFrom=fulltext)

![image.png](https://hackmd.io/_uploads/SyCnX-dmp.png)


## Gli1
DNA consensus sequence 5'-GACCACCCA-3' (PubMed:2105456, 8378770, 24217340).

Less in ACTE than ACNT.


[A conserved HH-Gli1-Mycn network regulates heart regeneration from newt to human](https://www.nature.com/articles/s41467-018-06617-z.pdf)

 GLI1 is required for GLI2 occupancy on the promoter regions of genes

BMP2 - Bone Morphogenetic Protein 2. Secreted Ligand of TGFb superfamily receptors. (transforming growth factor-beta). TGF-beta receptors leading to recruitment and activation of SMAD family transcription factors that regulate gene expression. bone and cartilage development [(TGFb induce osteoblast - bone/cartlidge **formation**.)](https://www.frontiersin.org/articles/10.3389/fimmu.2022.869422/full)
![image.png](https://hackmd.io/_uploads/SynmIZO76.png =200x)

"(ROS) can also act as second messengers for BMPs."
[2019 Interplay between BMPs and Reactive Oxygen Species in Cell Signaling and Pathology](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6843432/)
[2022 The Role Of BMPs in the Regulation of Osteoclasts Resorption and Bone Remodeling: From Experimental Models to Clinical Applications](https://www.frontiersin.org/articles/10.3389/fimmu.2022.869422/full)



**Gli1 Activated targets:**
BMP2 
Ptch2
Ptch1
Nek2

Nek1 - cell cycle, axon
Fez1? // Fasciculation And Elongation Protein Zeta 1
Fez2?

Gli1+Gli2
CCND1
E2F1
Sox2
Bcl2
Mycn - N-myc

## Gli2
Activator/repressor

 GLI1 is required for GLI2 occupancy on the promoter regions of genes

![image.png](https://hackmd.io/_uploads/B1PCExumT.png)


**Gli2 Activated targets:**
Ccn1 // Cyr61
Dnmt1
Nek2
Gli1 - [Gli2 leads to gli1]

Gli1+Gli2
CCND1 - Cyclin D1
E2F1
Sox2
Bcl2
Mycn - N-myc

**Repressed Gli2:**
CCDN2 - Cyclin D2
While Cyclin D2 has only been found to be significantly deregulated in glioma, Cyclin D1 in particular seems to be a pan-cancer actor.




XIAP - X-Linked Inhibitor Of Apoptosis // E3 Ubiquitin-Protein Ligase XIAP.
binding to tumor necrosis factor receptor-associated factors TRAF1 and TRAF2 and inhibits apoptosis induced by menadione, a potent inducer of free radicals, and interleukin 1-beta converting enzyme.


CDH1 - Calcium-Dependent Adhesion Protein. Cadherine E.
a preproprotein that is proteolytically processed to generate the mature glycoprotein
calcium-dependent cell-cell adhesion protein
ectodomain of this protein mediates bacterial adhesion to mammalian cells and the cytoplasmic domain is required for internalization


ABCG2 - **Porphyrin homeostasis**. xenobiotic transporter. Placenta. Flavin like drugs. Mitoxantrone. Anthracycline. 
[See Cholesterol and heme transporters](https://docs.google.com/spreadsheets/d/1ExKN0yQ0-Cv7HjRLVrnQza-T9s0_j9_Pf92G7IDfzx8/edit#gid=741940387)

CFLAR -  Cerebral Arteriopathy - apoptosis. crucial link between cell survival and cell death pathways in mammalian cells. structurally similar to caspase-8.

AKT1 - 	AKT Serine/Threonine Kinase 1. AKT activation relies on the PI3K pathway. [I.e. 3-phosphoinositol. IP3]

CXCR4 - Neuropeptide Y Receptor Y3. Lipopolysaccharide-Associated Protein 3. vascularization of the gastrointestinal tract, probably by regulating vascular branching and/or remodeling processes in endothelial cells. Involved in cerebellar development. In the CNS, could mediate hippocampal-neuron survival.Acts as a receptor for extracellular ubiquitin; leading to **enhanced** intracellular **calcium ions** and **reduced cellular cAMP levels** (PubMed:20228059)

BID - BH3 Interacting Domain Death Agonist. Regulates **apoptosis**. death agonist that heterodimerizes with either agonist BAX or antagonist BCL2

## Gli3
GLI3 functions mainly as a transcriptional repressor

transcriptional activator and a repressor of the sonic hedgehog (Shh) pathway, and plays a role in limb development



Furthermore, previous studies characterized four highly conserved non-coding DNA regions (HCNRs) within the human GLI3 locus that work as potential enhancer modules; it was demonstrated that HCNR2 and HCNR3 contain sufficient information to direct the expression of GLI3 in the dorsal spinal cord, and that the activity of these two modules is dependent on β-catenin/Tcf transcriptional activity (90–92).


# SHH & LRPs
[See Different LRPs for Wnt/Fzd](https://hackmd.io/@sholmqvist/BJpKurTBB/%2F0jxi3QtdQhW8wSTT1Ujc9g#Wnts-amp-Lrps)


## LRP1
Apolipoprotein E Receptor

Plasma clearance of chylomicron remnants and activated LRPAP1 (alpha 2-macroglobulin), as well as the local metabolism of complexes between plasminogen activators and their endogenous inhibitors


Statin inhibition of cholesterol production

LRP1B - LDL Receptor Related Protein 1B

encoded preproprotein is proteolytically processed by furin to generate 515 kDa and 85 kDa subunits that form the mature receptor (PMID: 8546712).

 intracellular signaling, lipid homeostasis, and **clearance of apoptotic cells**

the encoded protein is necessary for the alpha 2-macroglobulin-mediated clearance of secreted amyloid precursor protein and beta-amyloid, the main component of amyloid plaques found in **Alzheimer** patients.

Expression of this gene decreases with age and has been found to be lower than controls in brain tissue from Alzheimer's disease patients

[2012 - LRP1 mediates Hedgehog-induced endocytosis of the GPC3–Hedgehog complex](https://journals.biologists.com/jcs/article/125/14/3380/32417/LRP1-mediates-Hedgehog-induced-endocytosis-of-the)

### Lrp1b
LRP-Deleted In Tumors

silencing and down-expression of LRP1B as been observed in renal cell carcinoma and thyroid cancer. 

receptor-mediated endocytosis.


## LRP2
**Megalin** 
Low Density Lipoprotein Receptor-Related Protein 2 // Calcium sensor

This glycoprotein has a large amino-terminal extracellular domain, a single transmembrane domain, and a short carboxy-terminal cytoplasmic tail.

Ligands bind extracellular N-tail. including albumin, apolipoproteins B and E, and lipoprotein lipase

numerous ligands, including lipoproteins, sterols, vitamin-binding proteins, and hormones

protein also has a role in cell-signaling; extracellular ligands include *parathyroid horomones* and the morphogen *sonic hedgehog* while **cytosolic ligands** include **MAP kinase scaffold proteins** and **JNK interacting proteins**.


[2016 LRP2, an auxiliary receptor that controls sonic hedgehog signaling in development and disease](https://doi.org/10.1002/dvdy.24394)




# SHH and Cholesterol
[2023. Anual review. The Inseparable Relationship Between Cholesterol and Hedgehog Signaling](https://www.annualreviews.org/doi/pdf/10.1146/annurev-biochem-052521-040313)

[2022. Review. Cholesterol and Hedgehog Signaling: Mutual Regulation and Beyond.](https://www.frontiersin.org/articles/10.3389/fcell.2022.774291/full)



# Bbox?
[There is a real possibility that the SHH / oxygen poor niche in the Hypothalamus, where SHH normally is active is related to induction of Bbox. This is very speculative tho. This is a EBs exposed to SHH in vitro.]
![image](https://hackmd.io/_uploads/Hyq00Rq76.png =200x)
SHH induces Bbox1 in EBs


# Kevin Williams

Working on SHH pathway and fetal alcohol spectrum disorder FASD.

Sonic agoni


[2022 Burton ... Williams - Journal of neuroscience - Pharmacological activation of the Sonic hedgehog pathway with a Smoothened small molecule agonist ameliorates the severity of alcohol-induced morphological and behavioral birth defects in a zebrafish model of fetal alcohol spectrum disorder](https://onlinelibrary.wiley.com/doi/10.1002/jnr.25008)