Human Anatomy & Physiology (11th Edition)
11th Edition
ISBN: 9780134580999
Author: Elaine N. Marieb, Katja N. Hoehn
Publisher: PEARSON
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For each of the following, describe the path the protein takes to its final destination in the cell.
Drawings are strongly recommended! If you need more space, you can use a separate sheet of
paper. Proteins: 1) Hedgehog (released from the signaling cell), 2) Smoothened, 3) Ci/Gli
Your answers should include the following if they apply for each protein:
o Sorting sequences and how the protein knows where to go at each step (what recognizes
different sorting sequences/tags). How/when the protein is inserted into the membrane (if it is a membrane protein) What organelles the protein passes through on its way to its final destination. How the protein is transported (vesicles? translocons? etc.), including a role for microtubules.How the protein might be modified in each organelle it passes through. What other proteins are involved in transport and how the system is reset to allow for other
proteins to be transported.
Transcribed Image Text:The mechanism of Ci/Gli cleavage to release the repressor and ubiquitin-mediated proteolysis of the transcription
activator subunit is also unclear. In the absence of Hedgehog signaling, the Ci/Gli protein is localized to microtubules
in the cytosol by two other proteins, called Fu and Cos2. A set of kinases phosphorylate proteins in the complex,
which allows Ci/Gli to be recognized by the ubiquitin ligase (called Slimb in Drosophila). Proteolysis which only
destroys the transcription activator subunit of Ci/Gli, releasing Ci/GliR (the transcription repressor). Activation of
Smoothened allows Fu and Cos2 to bind to Smoothened on the plasma membrane, somehow freeing Ci/Gli from
phosphorylation and ubiquitylation. Ci/Gli then travels to the nucleus.
Because this signaling pathway is complicated and has a lot of unknowns, you can find Dr. Slenn's more detailed
drawing of the canonical signaling pathway below.
Hedge hog
plasma membrane
Smoothened
Fu Cos 2
Does not happen when Smoothened is active,
potenti ally because Smoothened binds to Fu and Casa
Slimb
various
kinases
CIR
Fo Cos2
microtubule
(CiR
CiR
proteasome
CiR
CiR
transcription
"of tor get
genes
enhancer
Hedgehog can also signal through non-canonical pathways that do not involve Ci/Gli. Smoothened is technically a
GPCR, though its activating ligand is unknown, and the best studied result of Smoothened activation does not
depend on G-proteins. However, Smoothened does activate G-proteins in some cells. The activated G-protein
binds to phospholipase C, turning it on. Through a series of steps that includes the opening of calcium channels
on the endoplasmic reticulum and regulation of several other proteins, the actin cytoskeleton rearranges, leading
to cell movement and changes in cell shape. Additionally, Patched can activate other non-canonical intracellular
signaling pathways that do not involve Smoothened at all (not discussed on this project).
3
12
Patched
Transcribed Image Text:Background information:
In class, we divided cell signaling pathways into four main categories while acknowledging that not every signaling
pathway fits into one of the four categories. For example, we discussed Notch signaling in animals and ethylene
signaling in plants. This project focuses on another new signaling pathway that does not fit into one of
our clear categories.
The Hedgehog signaling pathway is involved in the embryonic development of animals. The primary outcomes of
Hedgehog signaling are cell differentiation and proliferation due to changes in gene expression. These changes are
necessary for cell specialization during embryonic development.
Signaling cells produce Hedgehog proteins. Hedgehog proteins activate their receptor, called Patched, on
nearby target cells. The signal does not travel very far, and target cells that are closer to the signaling cell receive
a stronger signal. In the target cell, signal transduction begins on the plasma membrane of the primary cilium, a
specialized part of the cell you may not have learned much about. There is no need to look up this structure (and
if you choose to, Wikipedia is fine here); you should know what cilia are from
(A) Absence of Hedgehog
(B) Presence of Hedgehog
class.
Outside of cell
Hedgehog
Patched
Smoothened
Plasma
membrane
In the absence of Hedgehog signaling (left figure), Patched inhibits another
membrane protein called Smoothened. In the cytosol, one subunit of a
transcription factor called Ci in Drosophila and Gli in humans (Ci/Gli) is
destroyed via ubiquitin-mediated proteolysis. The remaining subunit of Ci/Gli
acts as a transcription repressor (Ci/GliR), blocking transcription of genes
Cytosol
Ci/Gli
Ci/Gli
РКА
CK1
GSK-3
Ubiquitylation
Cleavage
involved in differentiation and cell division.
Repressor
When Hedgehog is present (right figure), it blocks Patched from inhibiting
Smoothened. Smoothened is therefore activated, and through a series of
steps, Smoothened activation results in the stabilization of Ci/Gli. Ci/Gli can
therefore travel to the nucleus and activate transcription of target genes.
Nucleus
Repressor
O Transcription
repressed
- Transcription
activated
THE CELL: A MOLECULAR APPROACH 7e, Figure 16.41
© 2016 Sinauer Associates, Inc.
Despite decades of research, the mechanism through which Patched inhibits Smoothened is still a bit of a mystery.
One hypothesis is that Patched might be a transport protein that pumps a small molecule inhibitor of Smoothened
into the cell or that pumps an activator out of the cell. There is some experimental evidence that Patched functions
by preventing Smoothened access to cholesterol in the membrane, and when Hedgehog inhibits
Smoothened gains access to the cholesterol it needs to be activated. Patched might control cholesterol levels
through its transporter function.
2
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