Highlights

A partnership with growth potential

8 Jun 2010

The interaction points between proteins regulating cell growth could offer promising future targets for fighting cancer

Fig. 1: Growth of cultured human breast epithelial cells is regulated by localization of the YAP protein (green). In densely populated areas (top circle), Hippo-mediated signaling blocks growth by keeping YAP sequestered from the nucleus. In less-crowded regions (bottom circle), YAP is translocated to the nucleus and partners with TEAD to activate growth.

Fig. 1: Growth of cultured human breast epithelial cells is regulated by localization of the YAP protein (green). In densely populated areas (top circle), Hippo-mediated signaling blocks growth by keeping YAP sequestered from the nucleus. In less-crowded regions (bottom circle), YAP is translocated to the nucleus and partners with TEAD to activate growth.

© 2010 W. Hong

Malfunctions in a cellular pathway that controls organ growth can lead to unrestrained tumor cell proliferation. Wanjin Hong of the A*STAR Institute of Molecular and Cell Biology (IMCB), Singapore, recently partnered with his IMCB colleague Haiwei Song to collect detailed structural data about some of the key factors that power this process.

In healthy mammalian cells, the closely related YAP and TAZ proteins enter the nucleus and partner with TEAD transcription factors to stimulate cellular growth. Proper growth regulation requires that this nuclear localization is tightly controlled by the Hippo tumor suppressor pathway (Fig. 1). “Current results clearly support a role of overactivation of YAP/TAZ–TEAD [complexes] in cancer development,” says Hong. “YAP is amplified in some human and mouse cancer[s], and the TEAD4 gene is reported to be amplified in several human cancers.”

By performing X-ray crystallographic analysis of the domains that link these proteins, the researchers could directly zoom in on individual amino acids that contribute to the connections of the YAP–TEAD4 complex.

Their analysis enabled Song, Hong and co-workers to identify three amino acids in TEAD4 that appear to be essential to its interaction with YAP. Intriguingly, mutation of any of these residues led to a notable reduction of TEAD4’s capacity to induce cancerous transformation in cultured cells. For YAP, the interacting domain appears to consist primarily of two helical structures connected by a loop containing an evolutionarily conserved motif known as PXXΦP. Although the helices make a far greater contribution to the YAP–TEAD4 interface, this loop nevertheless appears essential for bringing the two proteins together. For both proteins, many of the amino acids identified correlate closely with previously identified activity-disrupting mutations.

Interestingly, although TAZ shares many of the key interacting residues identified for YAP, it entirely lacks the PXXΦP loop domain; this is in keeping with findings suggesting that these two proteins are not fully redundant, and indicates that many mysteries remain to be untangled for this regulatory network. “We are continuing to explore the possibility of resolving the structures of other proteins and complexes of the Hippo pathway,” says Song.

In the meantime, the investigators see this as an important first step, and they point out that the interaction sites they have identified may even have some clinical value. “The structure of this complex offers structural information for rational drug development to identify small molecules that may serve as potential drug leads to disrupt the interaction of YAP/TAZ–TEAD for treating human cancers,” says Hong.

The A*STAR-affiliated researchers mentioned in this highlight are from the Institute of Molecular and Cell Biology.

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References

Chen, L., Chan, S.W., Zhang, X.Q., Walsh, M., Lim, C.J., Hong, W. & Song, H. Structural basis of YAP recognition by TEAD4 in the Hippo pathway. Genes & Development 24, 290–300 (2010). | article

This article was made for A*STAR Research by Nature Research Custom Media, part of Springer Nature