Smoothened

Key takeaways

Smoothened belongs to biology; place it in that map before memorising details.
Learn the definition first, then one example that makes the definition concrete.
Connect Smoothened to a quantity you can measure, compute or draw — that is where exam questions come from.
Reproduce the core statement of Smoothened from memory before moving on to harder problems.

Reference excerpt

Smoothened is a protein that in humans is encoded by the SMO gene. Smoothened is a Class Frizzled (Class F) G protein-coupled receptor that is a component of the hedgehog signaling pathway and is conserved from flies to humans. It is the molecular target of the natural teratogen cyclopamine. It also is the target of vismodegib, the first hedgehog pathway inhibitor to be approved by the U.S. Food and Drug Administration (FDA). Smoothened (Smo) is a key transmembrane protein that is a key component of the hedgehog signaling pathway, a cell-cell communication system critical for embryonic development and adult tissue homeostasis. Mutations in proteins that relay Hh signals between cells cause birth defects and cancer. The protein that carries the Hh signal across the membrane is the oncoprotein and G-protein coupled receptor (GPCR) Smoothened (Smo). Smo is regulated by a separate transmembrane receptor for Hh ligands called Patched (Ptc). Ptc itself is a tumor suppressor that keeps the Hh pathway off by inhibiting Smo. The excessive Hh signaling that drives human skin and brain cancer is most frequently caused by inactivating mutations in Ptc or by gain of function mutations in Smo. While direct Smo agonists and antagonists, such as SAG and vismodegib, can bind to and activate or inhibit Smo, how Ptc inhibits Smo endogenously remains a mystery in the field. Smo is targeted and inhibited directly by a small-molecule drug, vismodegib, for the treatment of advanced basal cell cancer, however widespread resistance to this drug has become a prevalent issue. Therapeutic research aims to identify Ptc responsive sites on Smo in order to find another method to target Smo activity in Hh-driven cancers.

Function

Cellular localization plays an essential role in the function of SMO, which anchors to the cell membrane as a 7-pass transmembrane protein. Stimulation of the patched 12-pass transmembrane receptor by the sonic hedgehog ligand leads to translocation of SMO to the primary cilium in vertebrates in a process that involves the exit of patched from the primary cilium, where it normally localizes in its unstimulated state. Vertebrate SMO that is mutated in the domain required for ciliary localisation often cannot contribute to hedgehog pathway activation. Conversely, SMO can become constitutively localized to the primary cilium and potentially activate pathway signaling constitutively as a result of a tryptophan to leucine mutation in the aforementioned domain. SMO has been shown to move during patched stimulation from the plasma membrane near the primary cilium to the ciliary membrane itself via a lateral transport pathway along the membrane, as opposed to via directed transport by vesicles. The cAMP-PKA pathway is known to promote the lateral movement of SMO and hedgehog signal transduction in general. In invertebrates like Drosophila, SMO does not organize at cilia and instead is generally translocated to the plasma membrane following hedgehog binding to patched. After cellular localization, SMO must additionally be activated by a distinct mechanism in order to stimulate hedgehog signal transduction, but that mechanism is unknown. There is evidence for the existence of an unidentified endogenous ligand that binds SMO and activates it. It is believed that mutations in SMO can mimic the ligand-induced conformation of SMO and activate constitutive signal transduction. SMO plays a key role in transcriptional repression and activation by the zinc-finger transcription factor Cubitus interruptus (Ci; known as Gli in vertebrates). When the hedgehog pathway is inactive, a complex of Fused (Fu), Suppressor of Fused (Sufu), and the kinesin motor protein Costal-2 (Cos2) tether Ci to microtubules. In this complex, Cos2 promotes proteolytic cleavage of Ci by activating hyperphosphorylation of Ci and subsequent recruitment of ubiquitin ligase; the cleaved Ci goes on to act as a repressor of hedgehog-activated transcription. However, when hedgehog signaling is active, Ci remains intact and acts as a transcriptional activator of the same genes that its cleaved form suppresses. SMO has been shown to bind Costal-2 and play a role in the localization of the Ci complex and prevention of Ci cleavage. Additionally, it is known that vertebrate SMO contributes to the activation of Gli as a transcription factor via association with ciliary structures such as Evc2, but these mechanisms are not fully understood.

Endogenous activation

… excerpt ends here. Continue reading the full article.

Illustrations

Worked examples

Example 1 — a first encounter with Smoothened

Start with the simplest possible case. Write down what Smoothened claims or describes in one sentence, then invent the smallest concrete situation in which that sentence is true. In biology, the smallest case is usually a single object, a single equation or a single measurement. Check that every symbol or term in your sentence has a meaning in that case.

Example 2 — changing one variable

Take the situation from Example 1 and change exactly one quantity: double it, halve it, or set it to zero. Predict what should happen to Smoothened before you calculate. Comparing your prediction with the result is the fastest way to find out whether you understand the idea or only the words.

Example 3 — an exam-style question

Typical questions about Smoothened ask you to (a) state it precisely, (b) apply it to given data, and (c) explain a limitation. Practise writing all three answers in under five minutes; the third part is what separates a full-mark answer from an average one.

Applications of Smoothened

In research: Smoothened appears in biology research whenever the underlying quantities have to be modelled precisely. Papers usually cite it as a starting assumption and then explore where it breaks down.
In technology and industry: Engineering practice reuses Smoothened in design rules, simulations and safety margins. Knowing the idea lets you read a specification sheet and understand why the numbers look the way they do.
In the classroom: Smoothened is common in secondary-school and first-year university syllabi. It links to neighbouring topics 7TM receptors, Genes on human chromosome 7, Hedgehog signaling pathway, so understanding it makes those chapters shorter.
In everyday life: Look for Smoothened outside the textbook — in sport, cooking, traffic, electronics or the sky above you. An example you found yourself is remembered far longer than one you were given.

How to study Smoothened in 20 minutes

Read the reference excerpt below once, without taking notes.
Close the page and write down what Smoothened means in your own words.
Compare your version with the excerpt and mark what you missed.
Work through the three examples above with pen and paper.
Explain Smoothened out loud to somebody else — or to Teacher Smith in the lgStudy chat.

Frequently asked questions

What is Smoothened in simple terms?

Smoothened is a protein that in humans is encoded by the SMO gene. Smoothened is a Class Frizzled (Class F) G protein-coupled receptor that is a component of the hedgehog signaling pathway and is conserved from flies to humans.

Why does Smoothened matter?

Because it connects several biology ideas at once: it gives you a definition you can apply, a quantity you can calculate, and a way to check whether a result is plausible.

How should I study Smoothened?

Read the excerpt, restate it from memory, then work through the examples and applications listed on this page. The five-step study plan above takes about twenty minutes.

What does this page cover?

It gives you a compact reference excerpt plus original lgStudy explanations, examples, applications and study material on Smoothened.