Planar cell polarity (PCP), a process in which the epithelial tissues are polarized within the plane of the epithelium, plays an important role in development and organ function. Defects in PCP are associated with a variety of human diseases including cancer metastasis, neurological disorders, skeletal dysplasia, and congenital heart disease. Prof. Yusong Guo and his collaborators, Prof. Liwen Jiang at the Chinese University of Hong Kong and Prof. Yan Yan at LIFS of HKUST, discovered a novel molecular mechanism that controls the delivery of a key protein in PCP. Their findings, published in the Journal of Biological Chemistry, can provide useful guidance on the development of new drugs for cancer treatment.

To offer a new direction for more effective therapeutics, a research team led by Prof. Yusong Guo have unraveled how a key protein in PCP called Frizzled-6, is transported from within the cell to the cell surface where Frizzled-6 regulates PCP. Understanding the molecular mechanism behind this transportation process would help scientists find ways to inhibit the transportation of Frizzled-6 and shut down the PCP process if it is hijacked by cancer cells, thereby hindering cancer progression.

Prof. Yusong Guo (third left), Prof. Yan Yan (second left) and their research team

In the secretory transport pathway, the newly synthesized transmembrane PCP proteins are processed in the endoplasmic reticulum (ER) within the cell, where they are folded and modified. The processed proteins are then packaged into transport vesicles mediated by the COPII machinery. These transport vesicles act as vehicles to deliver their cargo proteins to the Golgi apparatus, en route to the cell surface.

Prof. Guo and his collaborators discovered that a polybasic motif in Frizzled-6 interacts with SAR1A, which is a key component of the COPII machinery. This interaction is essential for exporting Frizzled-6 out of the ER, the first step in the secretory pathway. Blocking the interaction between SAR1A and Frizzled-6 can bring the packaging and delivery to a halt, which is potentially effective in hindering cancer metastasis.

The researchers also found that newly synthesized Frizzled-6 is associated with another PCP protein, CELSR1 (cadherin EGF LAG seven-ass G-type receptor 1) in the secretory transport pathway. This association facilitates efficient Frizzled-6 delivery to the cell surface, providing a quality control mechanism that ensures appropriate stoichiometry of these two PCP proteins at cell surface.

“It has been known that PCP plays an important role in regulating cancer’s growth, but the molecular mechanism that regulates the transport of PCP proteins was largely unclear,” Prof. Guo said.  “Our study provides important insight in guiding the rational design of inhibitors to inhibit the cell surface delivery process, and offers a novel therapeutic strategy to downregulate PCP signaling for cancer treatment.”

Journal Reference:

Tang X, Zhang L, Ma T, Wang M, Li B, Jiang L, Yan Y, Guo Y. Molecular mechanisms that regulate export of the planar cell-polarity protein Frizzled-6 out of the endoplasmic reticulum. J Biol Chem. 2020 Jul 3;295(27):8972-8987. doi: 10.1074/jbc.RA120.012835.

Source: HKUST Press Release 07-Jul-2020