News archives


OCTOBER - DECEMBER 17

JULY - SEPTEMBER 17

APRIL - JUNE 17

JANUARY - MARCH 17

OCTOBER - DECEMBER 16

JULY - SEPTEMBER 16

APRIL - JUNE 16

JANUARY - MARCH 16

OCTOBER - DECEMBER 15

JULY - SEPTEMBER 15

APRIL - JUNE 15

JANUARY - MARCH 15

OCTOBER - DECEMBER 14

JULY - SEPTEMBER 14

APRIL - JUNE 14

JANUARY - MARCH 14

OCTOBER - DECEMBER 13

JULY - SEPTEMBER 13

APRIL - JUNE 13

JANUARY - MARCH 13

OCTOBER - DECEMBER 12

JULY - SEPTEMBER 12

APRIL - JUNE 12

JANUARY - MARCH 12

OCTOBER - DECEMBER 11

JULY - SEPTEMBER 11

APRIL - JUNE 11

JANUARY - MARCH 11

OCTOBER - DECEMBER 10

JULY - SEPTEMBER 10

APRIL - JUNE 10

JANUARY - MARCH 10

OCTOBER - DECEMBER 09

JULY - SEPTEMBER 09

APRIL - JUNE 09

JANUARY - MARCH 09

OCTOBER - DECEMBER 08

JULY - SEPTEMBER 08

APRIL - JUNE 08

JANUARY - MARCH 08

OCTOBER - DECEMBER 07

JULY - SEPTEMBER 07

APRIL - JUNE 07

JANUARY - MARCH 07

 
  current news   Press   selected story    
     
  4 December 2015  
  Congratulations to IMCB’s recent PhD graduate
 
 



Thesis Title: Mechanisms of oncogenic PRL-3 signalling under cellular stress

Supervisors: Zeng Qi1, 2 , Shen Han-Ming3

1  Institute of Molecular and Cell Biology, A*STAR, Singapore
2  Department of Biochemistry, National University of Singapore, Singapore
3  Department of Physiology, National University of Singapore, Singapore

Abstract
Phosphatase of regenerating liver 3 (PRL-3), an oncogenic phosphatase, is known to exhibit pleiotropic effects in cancer progression, including promoting cell proliferation, sustaining cell survival, inducing angiogenesis, and enhancing invasion and metastasis. However, the signalling mechanisms of PRL-3 remain largely unknown. Here, PRL-3 was identified as an activator of mTOR. PRL-3 induced an aberrant activation of mTOR signalling in cancer cells, as reflected by hyperphosphorylation of the direct substrates of mTORC1, 4E-BP1 and p70S6K. Despite growth-suppressing limitations, PRL-3 persistently activated mTORC1 in the presence of oxygen, serum, or amino acid deprivation. Functionally, PRL-3-mediated activation of mTORC1 resulted in increased cell motility, invasiveness, and MMP-2/9 production, suggesting a novel pathway for PRL-3-mediated cancer progression via mTORC1 activation. In the second part of the study, the mechanism underlying PRL-3-driven mTORC1 activation was characterised. PRL-3 was found to use a two-pronged approach in activating mTORC1: 1) increasing Rheb-GTP accumulation via activation of AKT-TSC2 signalling, and 2) enhancing Rag GTPases-mediated mTORC1 recruitment to lysosomes for Rheb-mediated activation. Thus, PRL-3 leads to sustained and efficient mTORC1 activation under both normal and stressed conditions. This novel mechanism might explain how PRL-3 promotes cancer progression through the mTOR pathway. Finally, a protective effect of PRL-3 against CoCl2-induced apoptosis was reported. This was p38 MAPK-dependent and mechanistically involved dephosphorylation of the pro-apoptotic kinase. These findings presented contribute to our understanding of PRL-3 signalling and highlight potential targets for therapeutic intervention in PRL-3-driven cancers.

Figure legend: A proposed model of the regulatory role of PRL-3 in mTOR signalling and p38 MAPK signalling. PRL-3 promotes mTORC1 activation by (1) activating Akt-TSC2-Rheb cascades and (2) enhancing Rag GTPases-mediated mTORC1 recruitment to lysosomes for activation, leading to an increase in cell motility, invasiveness, and MMP-2/9 production. (3) PRL-3 suppresses p38 MAPK activity to block apoptosis. Solid lines indicate direct regulation, while dotted line indicated indirect regulation.


For more information on Zeng Qi’s laboratory, please click here.