YAP1 and its fusion proteins in cancer initiation, progression and therapeutic resistance

Abstract

YAP1 is a transcriptional co-activator whose activity is controlled by the Hippo signaling pathway. In addition to important functions in normal tissue homeostasis and regeneration, YAP1 has also prominent functions in cancer initiation, aggressiveness, metastasis, and therapy resistance. In this review we are discussing the molecular functions of YAP1 and its roles in cancer, with a focus on the different mechanisms of de-regulation of YAP1 activity in human cancers, including inactivation of upstream Hippo pathway tumor suppressors, regulation by intersecting pathways, miRNAs, and viral oncogenes. We are also discussing new findings on the function and biology of the recently identified family of YAP1 gene fusions, that constitute a new type of activating mutation of YAP1 and that are the likely oncogenic drivers in several subtypes of human cancers. Lastly, we also discuss different strategies of therapeutic inhibition of YAP1 functions.

Keywords: Cancer; Gene fusions; Hippo signaling pathway; YAP1; YAP1 fusion.

Figure 1 –

Overview YAP1 protein domains and interaction partners

Figure 2 –

Hippo Core kinases and resulting regulation of YAP1. Figure was created with BioRender.com.

Figure 3 –

Mechanisms of YAP1 de-regulation in cancer

Figure 4 –

YAP1 and TAZ fusions in different cancer types. A: Overview of known YAP1 and TAZ gene fusions and the cancer types they are found in. B: Structural features that are shared between known YAP1 fusion proteins. All known YAP1 fusions retain the YAP1 TID domain necessary for binding to TEADs and lose the S397 residue of wild type YAP1 important for Hippo-mediated proteasomal degradation. In addition, the C-terminal fusion partner contains a nuclear localization sequence that mediates the nuclear localization of the YAP1 fusion proteins. The C-terminal fusion partner also contains a transactivation domain (TAD) that surrogates for the YAP1 TAD that is lost in the YAP1 fusions. C) Hallmarks of known YAP1 fusions. Figure was created with BioRender.com

Figure 5 -

Oncogenic mechanisms of YAP1 fusions. Left: Regulation of wild type YAP1 activity by the Hippo pathway. Right: YAP1 fusion proteins are resistant to Hippo pathway-mediated regulation, due to both constitutive nuclear localization (mediated by the nuclear localization sequence present in the C-terminal fusion partner sequence) and resistance to proteasomal degradation (mediated by the loss of YAP1 S397 in the fusion protein). Figure was created with BioRender.com