Mst1 is an interacting protein that mediates PHLPPs' induced apoptosis.
PHLPP1 and PHLPP2 phosphatases exert their tumor-suppressing functions by dephosphorylation and inactivation of Akt in several breast cancer and glioblastoma cells. However, Akt, or other known targets of PHLPPs that include PKC and ERK, may not fully elucidate the physiological role of the multifunctional phosphatases, especially their powerful apoptosis induction function. Here, we show that PHLPPs induce apoptosis in cancer cells independent of the known targets of PHLPPs. We identified Mst1 as a binding partner that interacts with PHLPPs both in vivo and in vitro. PHLPPs dephosphorylate Mst1 on the T387 inhibitory site, which activate Mst1 and its downstream effectors p38 and JNK to induce apoptosis. The same T387 site can be phosphorylated by Akt. Thus, PHLPP, Akt, and Mst1 constitute an autoinhibitory triangle that controls the fine balance of apoptosis and proliferation that is cell type and context dependent.
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Brigham and Women's Hospital, Boston, MA 02115, USA.
Meng
M
Qiao
Yaqi
Y
Wang
Xiaoen
X
Xu
Jing
J
Lu
Yongli
Y
Dong
Wufan
W
Tao
Janet
J
Stein
Gary S
GS
Stein
James D
JD
Iglehart
Qian
Q
Shi
Arthur B
AB
Pardee
D000818:Animals; D017209:Apoptosis; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D017228:Hepatocyte Growth Factor / Q000172:deficiency / Q000378:metabolism*; D006801:Humans; D051379:Mice; D009687:Nuclear Proteins / Q000378:metabolism*; D010749:Phosphoprotein Phosphatases / Q000378:metabolism*; D010766:Phosphorylation; D011493:Protein Kinase C / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000172:deficiency / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction
D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; C082332:macrophage stimulating protein; D017228:Hepatocyte Growth Factor; D051057:Proto-Oncogene Proteins c-akt; D011493:Protein Kinase C; D048049:Extracellular Signal-Regulated MAP Kinases; C400601:PHLPP1 protein, human; C541572:PHLPP2 protein, human; D010749:Phosphoprotein Phosphatases