A novel molecular mechanism that regulates secretion of the sonic hedgehog signaling molecule

HKUST-led research reveals a novel molecular mechanism that regulates secretion of sonic hedgehog, shedding light on cancer trea
A diagram demonstrating how hedgehog molecules are secreted from the producing cells and received by the target cells to induce the signal transduction pathway in target cells. Credit: HKUST

Research led by Hong Kong University of Science and Technology (HKUST) has revealed a novel mechanism that regulates secretion of sonic hedgehog (Shh), a key signaling molecule that plays an important role in cancer progression in mammals, opening the door to novel therapeutic strategies for cancer induced by the hedgehog signaling pathway.

The hedgehog (Hh) signaling pathway is instrumental in regulating embryonic patterning and facilitating the development of the central nervous system and organs of the human body. Such a pathway transmitting information between cells is initiated by the Hh ligands, which are first secreted from the producing cells and then bound with specific receptors on to induce Hh signaling.

Hh signaling is a major target for because this pathway, when hijacked by cells, can promote . However, all of the current Hh antagonists function to inhibit the activity of major factors mediating Hh signaling in target cells, but do not effectively block cancer progression that is promoted by the secreted Hh ligands.

Now, an international research team led by Prof. Guo Yusong, Associate Professor of Division of Life Science at HKUST, has revealed the mechanism governing the secretion of sonic hedgehog, a key member of Hh ligands in mammals, from the producing cells, offering new insights into inhibiting its secretion and shutting down the Hh signaling pathway when it is hijacked by , thereby hindering cancer progression.

The video shows the secretion of sonic hedgehog in a synchronized manner using a Retention Using Selective Hooks (RUSH) transport assay. Credit: HKUST

In the conventional secretory transport pathway, newly synthesized secretory proteins are firstly translocated into the endoplasmic reticulum (ER), where they are folded and modified. These proteins are then packaged into transport vesicles to be delivered to the Golgi apparatus to receive further modifications. Subsequently, they are enriched in transport vesicles at the trans Golgi network (TGN) and delivered to the to be secreted to the extracellular environment.

To study the secretion of Shh, Prof. Guo's team used a Retention Using Selective Hooks (RUSH) transport assay to analyze the secretion of sonic hedgehog in a synchronized manner. Using this approach and other classical cellular and molecular biology approaches, the researchers elucidated that the secretion of Shh is regulated by the following steps:

  1. Cargo receptor SURF4 packages Shh into COPII vesicles by directly binding to the CW motif of Shh at the ER.
  2. Upon reaching the Golgi, proteoglycans (PGs) compete with SURF4 to bind Shh and promote the dissociation of SURF4 and Shh.
  3. The released SURF4 returns to the ER through COPI vesicles.
  4. PGs promote TGN-to-cell surface transport of Shh.

The research findings not only reveal a novel SURF4-to-proteoglycan relay mechanism that regulates the secretion of Shh, but also indicate that blocking the SURF4-Shh interaction is an effective way to inhibit Shh .

HKUST-led research reveals a novel molecular mechanism that regulates secretion of sonic hedgehog, shedding light on cancer trea
A diagram depicting the molecular mechanisms regulating sorting and secretion of ShhN. Credit: HKUST

Prof. Guo said that "this presents the possibility of developing novel therapeutic strategies to block cancer progression, especially ligand-dependent cancer progression, induced by the Hh signaling pathway."

The results were recently published in Proceedings of the National Academy of Sciences.

More information: Xiao Tang et al, A SURF4-to-proteoglycan relay mechanism that mediates the sorting and secretion of a tagged variant of sonic hedgehog, Proceedings of the National Academy of Sciences (2022). DOI: 10.1073/pnas.2113991119

Citation: A novel molecular mechanism that regulates secretion of the sonic hedgehog signaling molecule (2022, May 9) retrieved 24 July 2024 from https://phys.org/news/2022-05-molecular-mechanism-secretion-sonic-hedgehog.html
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