Yes-associated protein (YAP65; referred to as YAP throughout) is a modular adapter protein first identified as a binding partner for the product of the proto-oncogene c-Yes
). YAP contains multiple protein interaction domains, including a proline-rich amino terminus, a 14-3-3 binding site (3
), WW domains (32
), SH3 binding motifs (12
), a coiled-coil, and a consensus PDZ binding motif at the extreme COOH terminus (43
). YAP mRNA is broadly distributed, and expressed sequence tags have been identified in cDNA libraries from many different species and from many tissues, cell lines, and tumor samples. Although the cellular and subcellular localization of the YAP protein has been less well characterized, it is expressed in multiple cell types and can be localized to both cytoplasmic and nuclear compartments (3
). This broad distribution and the modular structure of YAP together suggest multiple cellular functions.
The identification of YAP-interacting proteins has provided insight into potential roles for YAP in cell signaling within both cytosol and nucleus. YAP cytosolic interactions may impact cell signaling pathways by several possible mechanisms. For example, YAP binds the SH3 domain of c-Yes (57
) and can also associate with cytoplasmic PDZ proteins via its COOH terminus (43
). Therefore, YAP may play a role in the anchoring and/or targeting of c-Yes to position the kinase to respond to specific extracellular cues or to phosphorylate specific cellular substrates. Cytosolic YAP also may modulate growth factor receptor signaling. For example, YAP associates with the inhibitory Smad7 to attenuate transforming growth factor β signaling (14
) and may affect signaling via the ErbB-4 receptor (32
). In the nucleus, YAP may function as a coregulator, modulating the activity of several transcription factors. In this manner, YAP interacts with RUNX family members (64
), which impact hematopoiesis and osteogenesis, as well as TEAD family members (39
), which are implicated in muscle cell and neural crest cell differentiation. Furthermore, we recently found that the proline-rich amino terminus of YAP associates in the nucleus with heterogeneous nuclear ribonucleoprotein U (26
), a protein involved in mRNA processing and the control of gene expression. Finally, several pieces of data argue that regulated localization of YAP may impact apoptosis and cell cycle progression. Indeed, in the nucleus the YAP WW domain associates directly with the p53 gene family members p73α, p73β, and p63α and enhances the transcription of proapoptotic Bax
reporter constructs and endogenous Bax
). In addition, phosphorylation by Akt stimulates YAP interaction with cytosolic 14-3-3 and attenuates p73-mediated apoptosis (55
). YAP may also associate with p53BP2 (12
), a protein known to inhibit the activity of the p53 tumor suppressor. Thus, YAP likely exists in cell type- and compartment-specific protein complexes that define its function throughout development and in the adult organism, and yet specific in vivo requirements for YAP remain undefined.
YAP shows significant similarity to the product of the related gene, Taz
). With amino acid identity approaching 50%, YAP and TAZ may share common protein partners, and yet distinctions have been described (8
) The extent to which these proteins show unique or overlapping function in vivo remains unclear. Thus, the potential for redundancy between these proteins emphasizes the probable complexity of YAP function and highlights the need for understanding in vivo requirements for YAP.
Although an integrated view of YAP protein interactions and function is lacking, the data suggest that YAP is an adaptor protein that modulates multiple signal transduction pathways in many cell types. These pathways have been explored in biochemical assays and in cell culture model systems, but little is known regarding YAP function in the intact organism. To investigate in vivo requirements for YAP, we generated mice carrying a targeted disruption in the Yap gene. The embryonic lethal phenotype of homozygous mutant mice indicates that YAP is essential for embryogenesis and that, in fundamental developmental events, TAZ does not compensate for YAP. These results demonstrate for the first time a critical role for YAP in early embryonic development.