Partners in crime: POPX2 phosphatase and its interacting proteins in cancer

Abstract

Protein phosphorylation and dephosphorylation govern intracellular signal transduction and cellular functions. Kinases and phosphatases are involved in the regulation and development of many diseases such as Alzheimer’s, diabetes, and cancer. While the functions and roles of many kinases, as well as their substrates, are well understood, phosphatases are comparatively less well studied. Recent studies have shown that rather than acting on fewer and more distinct substrates like the kinases, phosphatases can recognize specific phosphorylation sites on many different proteins, making the study of phosphatases and their substrates challenging. One approach to understand the biological functions of phosphatases is through understanding their protein–protein interaction network. POPX2 (Partner of PIX 2; also known as PPM1F or CaMKP) is a serine/threonine phosphatase that belongs to the PP2C family. It has been implicated in cancer cell motility and invasiveness. This review aims to summarize the different binding partners of POPX2 phosphatase and explore the various functions of POPX2 through its interactome in the cell. In particular, we focus on the impact of POPX2 on cancer progression. Acting via its different substrates and interacting proteins, POPX2’s involvement in metastasis is multifaceted and varied according to the stages of metastasis.

Self-Sustained Regulation or Self-Perpetuating Dysregulation: ROS-dependent HIF-YAP-Notch Signaling as a Double-Edged Sword on Stem Cell Physiology and Tumorigenesis

“…The MAPKs (including JNK ( Santabarbara-Ruiz et al, 2015 ), Erk ( Aikawa et al, 1997 ), p38 kinase ( Kulisz et al, 2002 ; Emerling et al, 2005 ; Lee et al, 2012 ; Santabarbara-Ruiz et al, 2015 ), and big MAP kinase (BMK1/Erk5) ( Abe et al, 1996 ), the Ca 2+ /calmodulin-dependent kinase 2 (CaMK2) ( Basu et al, 2019 ), the cGMP-dependent protein kinase or protein kinase G (PKG), the PI3K/AKT ( Ray et al, 2012 ; Koundouros and Poulogiannis, 2018 ), the PKC ( Gong et al, 2015 ; Steinberg, 2015 ), the cAMP-dependent protein kinase (PKA ( Andre et al, 2013 )), and the focal adhesion kinase (FAK) ( Ben Mahdi et al, 2000 ) are redox sensitive and subject to activation by ROS. In parallel, protein serine/threonine phosphatases (PPP, including PP1 ( Kim et al, 2015 ), PP2A ( Low et al, 2014 ; Raman and Pervaiz, 2019 ), and PP2C-like partner of PIX 2 (POPX2 ( Kim P. R. et al, 2020 ))), and protein tyrosine phosphatases (PTP), including PTP1B, the low molecular weight PTP (LMW-PTP, the major PTP for FAK) ( Chiarugi et al, 2003 ), PTEN ( Ray et al, 2012 ), SHP-2 ( Chattopadhyay et al, 2017 ), and cdc25C ( Rudolph, 2005 ; Seth and Rudolph, 2006 ; Han et al, 2018 )) are also redox-sensitive and can be inhibited by oxidation. Through the ROS-mediated modulation of the kinase and phosphatase activity and the reciprocal phosphorylation-dependent ROS production, it is possible to have positive or negative feedback loops in the ROS-dependent cytokine/ECM signaling.…”

“…These mechanisms are to change the PTMs, the sequestration, and/or the compartmentalization states of YAP. Examples of the processes include 1) enhancing the degradation or dephosphorylation of LATS ( Kim P. R. et al, 2020 ; Zhao et al, 2020 ) ( Figure 4B ), 2 ) reducing YAP S127/S397 phosphorylation (e.g., by PP1A, PP2A, PPM1A ( Schlegelmilch et al, 2011 ; Li et al, 2016 ; Hu et al, 2017 ; Zhou et al, 2021 ), or Nemo-like kinase (NLK) ( Moon et al, 2017 )) ( Figure 4C ), 3 ) reducing YAP-Merlin association (by, e.g., enhancing Merlin S518 phosphorylation ( Morrison et al, 2001 ; Sherman and Gutmann, 2001 )) ( Figure 4D ), and 4 ) attenuating YAP-AMOT association (by, e.g., promoting actin filament polymerization to compete for binding to AMOT ( Mana-Capelli et al, 2014 )) ( Figures 4C,D ). A mechanism similar to example 4 is to reduce YAP-SWI/SNF association by nuclear actin filament polymerization ( Chang et al, 2018 ) ( Figure 4C ).…”

“…This effect places X-ROS upstream of YAP activation ( Figure 4B ). On the contrary, the dephosphorylation of LATS is primarily mediated by POPX2, which is also redox-sensitive and can be inhibited by ROS through cysteine oxidation ( Kim P. R. et al, 2020 ). This effect places ROS upstream of YAP suppression ( Figure 4B ).…”

“…YAP signaling dictates the selection of cell fate, and it is likely that YAP signaling follows switch-like behavior. For the therapeutic purpose, it will be convenient if ROS-mediated effects also act as a switch at different stages of stem cell development and tumor progression, whereby pharmaceutical interventions can be explicitly applied to turn “on” or “off” specific or unwanted effects ( Kim P. R. et al, 2020 ). In fact, switch-like enhancement of YAP-mediated epithelial-mesenchymal transition (EMT) has been proposed in cell migration on substrates engineered with nano-scale topographic cues ( Park et al, 2019 ).…”

“…The ability to auto-activate and recruit inhibitors to deactivate itself at the same time, as in the case of MST1/2 and STRIPAK, is not rare in biology. POPX2, for example, forms a trimeric complex with the Rac1/Cdc42 guanine nucleotide exchange factor ARHGEF7 (also known as the p21-activated protein kinase-exchange factor β (βPIX)) and PAK, wherein Rac1-activated PAK is subject to immediate dephosphorylation by POPX2 ( Kim P. R. et al, 2020 ). Another example is the complex formation of the scaffold molecule, muscle-selective A-kinase anchoring proteins (mAKAP), with cAMP-specific phosphodiesterase (PDE)-4D3 (PDE4D3) and PKA, wherein the PKA activity is subject to the downregulation of cAMP level by PDE4D3 ( Sette and Conti, 1996 ; Lim et al, 1999 ; Rababa'h et al, 2013 ).…”