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.

Fig. 1. Schematic illustrations of PP2Cα, POPX1, and POPX2.

Schematic drawings of the PPM1 phosphatases. POPX1 and POPX2 share high similarity with other PP2C family proteins. The yellow region indicates the PP2C phosphatase catalytic domain and the black bars represent the similarity regions between proteins. The purple region indicates the region of homology between POPX1 and POPX2. The numbers to the right refer to the number of amino acid residues in each protein.

Fig. 2. Schematic illustration of KIF3A-mediated cargo delivery in control and POPX2 overexpressing cells.

KIF3A motor protein is phosphorylated at Ser690 by CaMKII, leading to an open conformation and active motor. Active kinesin-2 motor complex delivers N-cadherin and Par-3 to the cell surface by trafficking along the microtubules. POPX2 dephosphorylates KIF3A at Ser690 and induces a closed and auto-inhibited conformation. In addition, POPX2 also dephosphorylates and inhibits CaMKII. Therefore, POPX2 overexpressing cells have impaired N-cadherin and Par-3 transport to the cell periphery leading to loss of cell–cell adhesion and cell polarity.

Fig. 3. Regulation of the Hippo pathway by POPX2.

POPX2 dephosphorylates LATS1 at Thr1079 and negatively regulates the activity of LATS1. In wild-type (WT) cells, dephosphorylation and inactivation of LATS1 result in translocation of YAP/TAZ to the nucleus to induce TEAD-mediated gene transcription. On the other hand, POPX2-knockout (KO) cells show high levels of phospho-LATS1, leading to the phosphorylation of YAP/TAZ. Phosphorylated YAP/TAZ are targeted for degradation in the cytoplasm. As a result, there is decreased TEAD-mediated transcription.

Fig. 4. The role of POPX2 in DNA damage response.

DNA damage stimulates activation and translocation of ataxia-telangiectasia mutated (ATM) kinase to the cytosol to initiate DNA damage response. TNF-receptor associated factor (TRAF) forms a complex with TAK1 and its binding proteins TAB1/2/3. Active TAK1 phosphorylates the IKK complex, leading to translocation of NF-κB from the cytosol to the nucleus. This results in the upregulation of NF-κB-mediated antiapoptotic gene expression. In the presence of high levels of POPX2, TAK1 is negatively regulated and its downstream effect is inhibited.

Fig. 5. Proposed working model of POPX2 in cancer progression.

High levels or activity of POPX2 at early stages of metastasis favor cancer cell invasion, migration, and survival in circulation (stages 1, 2, and 4). However, lower levels or activity of POPX2 in cancer cells which have established at metastatic sites promote colonization through upregulation of pro-angiogenic factors and secreted proteins (stage 6). Meanwhile, lower levels or activity of POPX2 also enhance TAK1-mediated antiapoptotic gene expression, which in turn allows the cancer cells to proliferate despite suffering DNA damage (stage 7).