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Studies Identifying Structure, Role of Integrin-Activating Proteins Could Lead to New Therapeutic Targets for Cancer

December 8, 2020

Jinhua Wu, PhDJinhua Wu, PhD

PHILADELPHIA (December 8, 2020) – Researchers from Fox Chase Cancer Center have recently publish a series of collaborative studies that could help facilitate the development of new therapeutic agents for cancer treatment by altering integrin activity.

The studies determined the high-resolution structures of the functional regions of two important proteins—talin and RIAM—and revealed new insights into integrin activation mediated by these two proteins. Integrins are glycoproteins found on the surface of cells and are involved with several functions such as adhesion to other cells or to material outside of the cells.

“Integrins are involved in progression and metastasis of many types of cancer,” said Jinhua Wu, PhD, associate professor in the Molecular Therapeutics program at Fox Chase. “Understanding the structure and function of talin and RIAM would have great potential for design of integrin inhibitors that may suppress related cancer progression and metastasis.”

In the first study, done by Wu’s lab in collaboration with two teams in Europe, the researchers report on the structure of the head domain of talin at an atomic level and how it interacts with integrin via specific amino acid residues. Pingfeng Zhang, PhD, a former research associate at Fox Chase, was the first author.

This structure provides, for the first time, a snapshot of talin in an active state, known as the “FERM-folded” structure, and elucidates how this active state, distinctly different from previously reported structure of talin, is essential for talin-integrin interaction and integrin activation. This knowledge provides an understanding of the regulatory mechanisms of integrin function and could be used, for example, in design of novel therapeutic tools.

The first study, “Crystal Structure of the FERM-Folded Talin Head Reveals the Determinants for Integrin Binding,” was published in Proceedings of the National Academy of Sciences (PNAS). The talin structure reported in that study also provided the foundation for a new discovery, which was reported in the second study, which was published in the Journal of Cell Science, that an “F1 loop” region in the active talin plays a crucial role in integrin activation.

Computational and biochemical studies showed direct and catalytic interactions of the talin region with the juxtamembrane moiety of integrin. This paper, “The F1 Loop of the Talin Head Domain Acts as a Gatekeeper in Integrin Activation and Clustering,” and the PNAS study provide a comprehensive molecular model by which talin activates integrin.

Wu conducted these two studies with Bernhard Wehrle-Haller, PhD, of the University of Geneva, and Vesa P. Hytönen, PhD, of Tampere University in Finland.

Finally, in a third study, Wu’s lab determined five crystal structures of RIAM in different conditions. Analyses of these structures led to a new finding that the RIAM function of binding to cell membrane is self-suppressed and that this function can be activated by Src kinases. This allows RIAM to accumulate on the cell membrane and subsequently promote integrin activation.

The study, “Phosphorylation of RIAM by Src Promotes Integrin Activation by Unmasking the PH Domain of RIAM,” was published in Structure. Eun-Ah Cho, PhD, a postdoctoral associate in Wu’s lab, was the first author.

The Hospital of Fox Chase Cancer Center and its affiliates (collectively “Fox Chase Cancer Center”), a member of the Temple University Health System, is one of the leading cancer research and treatment centers in the United States. Founded in 1904 in Philadelphia as one of the nation’s first cancer hospitals, Fox Chase was also among the first institutions to be designated a National Cancer Institute Comprehensive Cancer Center in 1974. Fox Chase researchers have won the highest awards in their fields, including two Nobel Prizes. Fox Chase physicians are also routinely recognized in national rankings, and the Center’s nursing program has received the Magnet recognition for excellence five consecutive times. Today, Fox Chase conducts a broad array of nationally competitive basic, translational, and clinical research, with special programs in cancer prevention, detection, survivorship and community outreach. It is the policy of Fox Chase Cancer Center that there shall be no exclusion from, or participation in, and no one denied the benefits of, the delivery of quality medical care on the basis of race, ethnicity, religion, sexual orientation, gender, gender identity/expression, disability, age, ancestry, color, national origin, physical ability, level of education, or source of payment.

 

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