Smoothened: A Key Protein in Development and Disease

Smoothened (SMO) is a protein in the outer membrane of cells belonging to the G protein-coupled receptor family. These molecules specialize in receiving and transmitting signals, acting like cellular antennas that detect external cues and relay messages to the cell’s interior. The structure of Smoothened features seven helices that pass through the cell membrane, an arrangement highly conserved across species.

Smoothened and the Hedgehog Signaling Pathway

Smoothened is a central component of the Hedgehog signaling pathway, a network that directs cell growth and differentiation during development. Smoothened acts as the main signal transducer, but its activity is controlled by the protein Patched (PTCH1). Under normal conditions, PTCH1 is located in a hair-like structure on the cell surface called the primary cilium, where it actively suppresses Smoothened.

When a Hedgehog ligand binds to the PTCH1 receptor, it causes PTCH1 to move out of the primary cilium. The removal of the inhibitory PTCH1 protein allows Smoothened to become active and accumulate within the cilium. This relocation is a required step for Smoothened to function in vertebrates.

Once Smoothened is active and correctly positioned, it initiates a cascade of events inside the cell that leads to the activation of Gli transcription factors. These proteins then travel to the cell’s nucleus, where they control which genes are turned on or off. By regulating gene expression, the Hedgehog pathway directs a cell’s development and function.

Smoothened’s Functions in Development

The activity of the Smoothened protein is deeply involved in the construction of an embryo. The signals it transduces are responsible for ensuring that various parts of the developing body form correctly. The precise control of when and where Smoothened is activated allows for the intricate patterning required to build a complex organism.

One of Smoothened’s roles is in the development of the central nervous system. It helps guide the formation of the neural tube, the embryonic structure that gives rise to the brain and spinal cord. Signals mediated by Smoothened ensure that different types of neurons are generated in the correct locations, allowing for the assembly of functional neural circuits.

Smoothened activity is also important for the development of the skeleton and limbs. For instance, the gradient of signaling it helps create across a developing limb bud dictates the identity and number of digits. The protein’s influence extends to the formation of many internal organs, including the lungs and the gastrointestinal tract, and plays a part in craniofacial development.

Smoothened’s Impact on Human Health and Disease

Smoothened and the Hedgehog pathway continue to function in adult tissues, contributing to processes like tissue repair and the regulation of adult stem cells. When the pathway’s regulation goes awry, it can have significant consequences for human health. The improper activation or deactivation of Smoothened is linked to a range of diseases, from congenital disorders to cancer.

Uncontrolled activation of Smoothened is a driver of certain cancers, signaling for cells to proliferate without restraint. The most prominent example is basal cell carcinoma (BCC), the most common form of skin cancer, where mutations that activate Smoothened or inactivate its inhibitor, PTCH1, are frequently found. A similar mechanism drives a significant subset of medulloblastoma, a pediatric brain tumor, and the pathway is implicated in other malignancies like rhabdomyosarcoma.

Conversely, insufficient signaling can lead to severe developmental disorders. Holoprosencephaly is a condition with profound malformations of the brain and face, resulting from a failure of the embryonic forebrain to divide. This defect is often linked to inadequate Hedgehog signaling. Another example is Gorlin syndrome, a genetic disorder caused by inheriting a mutated PTCH1 gene, which leads to developmental abnormalities and a high risk of developing multiple basal cell carcinomas.

Therapeutic Approaches Targeting Smoothened

Given the link between hyperactive Smoothened and cancer, the protein has become a target for drug development. This strategy has led to the creation of a class of drugs known as Smoothened inhibitors. These therapies are designed to block the protein’s signaling activity, thereby halting the uncontrolled cell growth that drives the tumor.

These targeted therapies have shown success in treating cancers dependent on the Hedgehog pathway. Two of the most well-known Smoothened inhibitors are vismodegib and sonidegib. These drugs are approved for treating advanced basal cell carcinoma, particularly cases that are locally advanced or have metastasized and cannot be treated with surgery or radiation. Vismodegib also has use in treating specific subtypes of medulloblastoma.

Despite their effectiveness, a challenge with these inhibitors is the development of drug resistance. Cancer cells can acquire new mutations that allow them to reactivate the signaling pathway, even in the presence of the drug. Research is focused on developing next-generation inhibitors or targeting other components of the Hedgehog pathway to overcome these resistance mechanisms.