Yu-Han Huang1,2,*, Abdul Qader O. Al-aidaroos1,*, Hiu-Fung Yuen1,*, Shu-Dong Zhang3, Han-Ming Shen4, Ewelina Rozycka3,6, Cian M. McCrudden3, Vinay Tergaonkar1, Abhishek Gupta1,You Bin Lin1, Jean Paul Thiery1,5, James T. Murray6 and Qi Zeng1,5
(*These authors contributed equally to this work)
1 Institute of Molecular and Cell Biology, A*STAR (Agency for Science, Technology and Research), Republic of Singapore
2 NUS Graduate School for Integrative Sciences and Engineering, National University of Singapore, Republic of Singapore
3 Center for Cancer Research and Cell Biology, Queen’s University Belfast, Belfast, United Kingdom
4 Department of Epidemiology and Public Health, National University of Singapore, Republic of Singapore
5 Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Republic of Singapore
6 Current address: School of Biochemistry and Immunology, Trinity College Dublin, Dublin, Ireland
Published in Autophagy in October 2014
Autophagy, a “self-eating” cellular process, has dual roles in promoting and suppressing tumor growth, depending on cellular context. PTP4A3/PRL-3, a plasma membrane and endosomal phosphatase, promotes multiple oncogenic processes including cell proliferation, invasion and cancer metastasis. In this study, we demonstrate that PTP4A3 accumulates in autophagosomes upon inhibition of autophagic degradation. Expression of PTP4A3 enhances PIK3C3-BECN1-dependent autophagosome formation and accelerates LC3-I to LC3-II conversion in an ATG5-dependent manner. PTP4A3 overexpression also enhances the degradation of SQSTM1, a key autophagy substrate. These functions of PTP4A3 are dependent on its catalytic activity and prenylation-dependent membrane association. These results suggest that PTP4A3 functions to promote canonical autophagy flux. Unexpectedly, following autophagy activation, PTP4A3 serves as a novel autophagic substrate, thereby establishing a negative feedback-loop that may be required to fine-tune autophagy activity. Functionally, PTP4A3 utilizes the autophagy pathway to promote cell growth, concomitant with the activation of AKT. Clinically, from the largest ovarian cancer dataset (GSE 9899, n = 285) available in GEO, high levels of expression of both PTP4A3 and autophagy genes significantly predict poor prognosis of ovarian cancer patients. These studies reveal a critical role of autophagy in PTP4A3-driven cancer progression, suggesting that autophagy could be a potential Achilles heel to block PTP4A3-mediated tumor progression in stratified patients with high expression of both PTP4A3 and autophagy genes.
Figure Title: Metastatic PTP4A3 Phosphatase In Autophagosomes
Figure Legend: PTP4A3 is a novel autophagy enhancer which exploits autophagy to promote cell proliferation. Interestingly, PTP4A3 also gets degraded via the autophagy pathway, constituting a possible negative feedback loop. Pictured here are chloroquine-treated Chinese Hamster Ovary (CHO) cells overexpressing PTP4A3 (red) and GFP-LC3 (green). Note how they co-localize tightly in autophagosomal puncta (yellow).
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