New molecular mechanism regulating secretion of sonic hedgehog signal molecules

Diagram showing how hedgehog molecules are secreted from producing cells and received by target cells to induce signal transduction pathways in target cells. Credit: HKUST

Research led by the Hong Kong University of Science and Technology (HKUST) has revealed a novel mechanism that regulates the secretion of sonic hedgehog (Shh), a key signaling molecule that plays a critical role in cancer development in mammals, opening the door to new therapeutic strategies. for cancers caused by hedgehog signaling pathways.

The hedgehog (Hh) signaling pathway plays an important role in regulating embryonic patterns and facilitating the development of the central nervous system and human organs. Such pathways that transmit information between cells are initiated by Hh ligands, which are first secreted from producing cells and then bind to specific receptors on target cells to induce Hh signaling.

Hh signaling is a prime target of cancer therapy because this pathway, when hijacked by cancer cells, can promote cancer development. However, all current Hh antagonists function to inhibit the activity of key factors that mediate Hh signaling in target cells, but do not effectively block cancer progression driven by secreted Hh ligands.

Now, an international research team led by Prof. Guo Yusong, Associate Professor of the Division of Life Science at HKUST, has revealed the mechanisms that regulate the secretion of sonic hedgehogs, a key member of the Hh ligand in mammals, from producing cells, offering a new product of insight into inhibiting their secretion and shutting down Hh signaling pathways when plowed. by cancer cells, thereby inhibiting the development of cancer.

Video demonstrates synchronized sonic hedgehog secretion using the Retention Using Selective Hooks (RUSH) transport test. Credit: HKUST

In the conventional secretory transport pathway, newly synthesized secretory proteins are first translocated into the endoplasmic reticulum (ER), where they are folded and modified. These proteins are then packaged into transport vesicles for delivery to the Golgi apparatus for further modification. Furthermore, they are enriched in transport vesicles in the trans Golgi network (TGN) and delivered to the plasma membrane for secretion into the extracellular environment.

To study the secretion of Shh, the team of Prof. Guo used the Selective Latching Retention transport assay (RUSH) to synchronously analyze the secretions of sonic hedgehogs. Using this and other classical cellular and molecular biology approaches, the researchers explain that Shh secretion is regulated by the following steps:

  1. The SURF4 cargo receptor packs Shh into COPII vesicles by direct binding to the CW Shh motif in the ER.
  2. Upon reaching the Golgi, proteoglycans (PG) compete with SURF4 for binding to Shh and promoting the dissociation of SURF4 and Shh.
  3. The released SURF4 returns to the ED via COPI vesicles.
  4. PG promotes TGN-to-cell surface transport of Shh.

The study findings not only revealed a novel SURF4-to-proteoglycan relay mechanism regulating Shh secretion, but also demonstrated that blocking the SURF4-Shh interaction is an effective means of inhibiting Shh secretion.

HKUST-led research reveals novel molecular mechanism regulating sonic hedgehog secretion, sheds light on cancer treatment

Diagram illustrating the molecular mechanisms regulating ShhN sorting and secretion. Credit: HKUST

Prof. Guo said that “this presents the possibility of developing new 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.

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Further information:
Xiao Tang et al, The mechanism of the SURF4-to-proteoglycan relay mediating the sorting and secretion of tagged variants from sonic hedgehogs, Proceedings of the National Academy of Sciences (2022). DOI: 10.1073/pnas.2113991119

Provided by Hong Kong University of Science and Technology

Quote: A novel molecular mechanism regulating secretion of sonic hedgehog signaling molecules (2022, 9 May) retrieved on 9 May 2022 from

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