YAP modifies cancer cell sensitivity to EGFR and survivin inhibitors and is negatively regulated by the non-receptor type protein tyrosine phosphatase 14.
The Yes-associated protein (YAP) is a transcriptional factor involved in tissue development and tumorigenesis. Although YAP has been recognized as a key element of the Hippo signaling pathway, the mechanisms that regulate YAP activities remain to be fully characterized. In this study, we demonstrate that the non-receptor type protein tyrosine phosphatase 14 (PTPN14) functions as a negative regulator of YAP. We show that YAP forms a protein complex with PTPN14 through the WW domains of YAP and the PPXY motifs of PTPN14. In addition, PTPN14 inhibits YAP-mediated transcriptional activities. Knockdown of YAP sensitizes cancer cells to various anti-cancer agents, such as cisplatin, the EGFR tyrosine kinase inhibitor erlotinib and the small-molecule antagonist of survivin, S12. YAP-targeted modalities may be used in combination with other cancer drugs to achieve maximal therapeutic effects.
Cedars-Sinai Women's Cancer Program at the Samuel Oschin Comprehensive Cancer Institute Los Angeles, CA 90048, USA.
J-M
JM
Huang
I
I
Nagatomo
E
E
Suzuki
T
T
Mizuno
T
T
Kumagai
A
A
Berezov
H
H
Zhang
B
B
Karlan
M I
MI
Greene
Q
Q
Wang
D000217:Acyltransferases; D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D020816:Amino Acid Motifs; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D002945:Cisplatin / Q000494:pharmacology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000069347:Erlotinib Hydrochloride; D055785:Gene Knockdown Techniques; D017930:Genes, Reporter; D057809:HEK293 Cells; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D049410:Luciferases, Renilla / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D041681:NIH 3T3 Cells; D010446:Peptide Fragments / Q000737:chemistry; D010750:Phosphoproteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D025941:Protein Interaction Mapping; D054558:Protein Tyrosine Phosphatases, Non-Receptor / Q000737:chemistry / Q000378:metabolism*; D011799:Quinazolines / Q000494:pharmacology*; D034741:RNA, Small Interfering / Q000235:genetics; D000077022:Survivin; D014157:Transcription Factors / Q000378:metabolism; D015533:Transcriptional Activation; D000091102:YAP-Signaling Proteins
D048868:Adaptor Proteins, Signal Transducing; D000970:Antineoplastic Agents; C107489:BIRC5 protein, human; D051034:Inhibitor of Apoptosis Proteins; D010446:Peptide Fragments; D010750:Phosphoproteins; D011799:Quinazolines; D034741:RNA, Small Interfering; D000077022:Survivin; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human; D000069347:Erlotinib Hydrochloride; D049410:Luciferases, Renilla; D000217:Acyltransferases; C108675:TAFAZZIN protein, human; D066246:ErbB Receptors; C093261:PTPN14 protein, human; D054558:Protein Tyrosine Phosphatases, Non-Receptor; D002945:Cisplatin