YAP is a potent growth promoter. Overexpression of YAP increases organ size in Drosophila
and saturation cell density in NIH-3T3 cell culture [8
]. However, yap
was termed a candidate oncogene only after it was shown to be in human chromosome 11q22 amplicon, which is evident in several human cancers [12
]. Consistently, yap
was shown to be amplified in human primary intracranial ependymomas by clinical study [62
]. Besides the genomic amplification, YAP expression and nuclear localization was also shown to be elevated in multiple types of human cancers [8
]. Several experiments further confirmed that YAP has oncogenic function: YAP overexpression in MCF10A cells induces epithelial-mesenchymal transition (EMT), which is often associated with cancer metastasis [12
]; YAP cooperates with myc
oncogene to stimulate tumor growth in nude mice [13
]; and more interestingly, transgenic mice with liver-specific YAP overexpression show a dramatic increase in liver size and eventually develop tumors [10
]. The above evidence strongly indicates the function of yap
as an oncogene. However, YAP was also reported to be a tumor suppressor as its gene locus is deleted in some breast cancers with a correlated loss of YAP expression [64
]. Further experiments such as conditional knockout animal model will finally clarify the role of YAP in tumorigenesis.
The oncogenic function of YAP is further supported by the tumor suppressor function of its inhibitory upstream Hippo pathway components. Lats1 knockout leads to soft-tissue sarcoma and ovarian tumor development [65
, an activating subunit of Lats, is mutated in both human and mouse cancer cells [23
]. Loss-of-function mutation of WW45 has been observed in several human cancer cell lines [17
]. Furthermore, a recent report showed that knockout of ww45
leads to hyperplasia and differentiation defects in mouse embryonic epithelial structures [58
]. Mer, which is further upstream of the Hippo pathway, is a well-established human tumor suppressor [66
]. Therefore, the Hippo pathway consists of many proven or candidate tumor suppressors that inhibit YAP oncoprotein.
Noteworthy, several studies showed a proapoptotic function of YAP, which was mainly explained by co-activation of p73 [44
]. So far, the proapoptotic activity of YAP was only observed by overexpression of YAP or in response to strong apoptotic stimuli, such as Fas activation or DNA damage. However, the effect of YAP overexpression in vivo
was shown to be an increase of organ size and finally tumor formation without accompanied increase of apoptosis. In fact, YAP overexpression protects liver tissue from Fas induced apoptosis [10
]. On the other hand, the Drosophila
genetic studies have clearly established that Yki inhibits aopotosis in vivo
. It is still possible that under certain conditions like DNA damage, YAP was tyrosine phosphorylated by c-Abl, which selectively activates YAP transcriptional activity on p73 to induce apoptosis.
Contact inhibition of cell growth, often referred to as a hallmark of cancer cells, has long been a mystery. However, the Hippo pathway may have opened the window a little bit to understand this phenomenon. Several components of this pathway have been implicated in contact inhibition. Mer becomes dephosphorylated and activated in confluent cells [67
], which has been reported to be both necessary and sufficient for contact inhibition. Lats2 and WW45 are also related to contact inhibition as their knockout MEF cells show loss of contact inhibition [58
]. Finally, YAP is phosphorylated and translocated to the cytoplasm by the Hippo pathway at high cell density in a Mer-dependent manner [8
]. More importantly, a dominant-negative form of YAP restores contact inhibition in ACHN [8
], a cancer cell line with activation of YAP due to WW45 mutation. These observations suggest a critical role of YAP and the Hippo pathway in contact inhibition. Indentifying the upstream signal of this pathway might solve a long-standing mystery in cell biology.