Researchers elucidate mechanotransduction pathways of transmembrane proteins

By Samantha Black, PhD, The Science Advisory Board staff writer

January 6, 2020 -- Researchers from Imperial College London, Queen Mary University of London, and Tampere University in Finland present new mechanistic pathways for transmembrane proteins with implications in drug discovery and development. The results of the study were published in Nature Materials on January 6.

Syndecan proteins belong to a family of transmembrane proteoglycan adhesion receptors. Syndecan-4 is ubiquitously expressed in nearly all cells of the body and acts synergistically with integrins to regulate substrate adhesion and cytoskeletal organization. It has a suspected role in mechanotransduction, the process by which cells convert mechanical stimuli to electrochemical activity, but the specific underlying molecular mechanisms are unknown. Using a combination of biophysical, cell biology and computational techniques, the researchers set out to elucidate the syndecan-4 mechanotransduction pathway.

Cellular 'hands' convert movements outside the cell (top) into biochemical signals inside the cell (bottom).

"As syndecan-4 is expressed on almost all of our cells, the mechanisms we've uncovered could be targeted to alter any number of diseases and biological processes," said co-author Stephen Thorpe of Queen Mary University of London.

The researchers found that syndecan-4 acts together with plasma membrane receptors (ECFR and β1 integrins) to establish force-dependent crosstalk which induces RhoA activation, adaptive stiffening, and yes-associated protein (YAP) transcriptional signaling. These processes may play a key role in disease development.

YAP activates the transcription of genes involved in cell proliferation and suppressing apoptotic genes. YAP is also an oncogene, which is amplified in many cancers. Syndecan-4-mediated tension at the cell-extracellular matrix interface is essential for YAP transcriptional signaling.

Moreover, the team found that the formation of a syndecan-4–α-actinin–F-actin molecular scaffold results in cell stiffening. This can lead to the activation of phosphatidylinositol 3-kinase (PI3K), which regulates cell growth, proliferation, motility, survival and intracellular trafficking, and has implications in cancer.

syndecan-4 mechanosignalling is both chemically and mechanically propagated throughout the cell via diffusion of PIP3 lipid second messengers and mechanical transmission through the tensile cytoskeleton via a syndecan-4–α-actinin–F-actin molecular scaffold.

"The way cells interact with their environment could inform how we engineer tissues and mimic human organs for drug design. Syndecan-4 could now play a fundamental part in this endeavor," said Armando del Río Hernández, lead investigator.

In the future, the researchers will investigate syndecan-4's links to specific diseases. For example, Vesa Hytönen of Tampere University said that "better understanding of cellular mechanosensing opens possibilities to develop treatments for conditions like cancer and fibrosis."

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