The multiple cellular functions of the oncoprotein Golgi phosphoprotein 3

Abstract

The highly conserved Golgi phosphoprotein 3 (GOLPH3) protein, a component of Trans-Golgi Network (TGN), has been defined as a "first-in-class Golgi oncoprotein" and characterized as a Phosphatidylinositol 4-phosphate [PI(4)P] effector at the Golgi. GOLPH3 is commonly amplified in several solid tumors. Furthermore this protein has been associated with poor prognosis in many cancers. Highly conserved from yeast to humans, GOLPH3 provides an essential function in vesicle trafficking and Golgi structure. Recent data have also implicated this oncoprotein in regulation of cytokinesis, modulation of mitochondrial mass and cellular response to DNA damage. A minute dissection of the molecular pathways that require GOLPH3 protein will be helpful to develop new therapeutic cancer strategies.

Figure 1. Biochemical characteristics of GOLPH3 family proteins

(A) Percent identity matrix obtained by Clustal 2.1, comparing the GOLPH3 family proteins from several species. Hs, H. sapiens; Rn, R.novergicus; Dm, D. melanogaster; Ce, C. elegans; Sc, S. cerevisiae; Hs L, H. sapiens GOLPH3L; RnL, R. novergicus GOLPH3L (B) Schematic representation of human GOLPH3 protein. (Yellow), the Gpp34 PI(4)P-binding domain;R7, R14, R15, the arginine residues required for coatomer binding; W81, R90, R171, R174, the conserved amino acid residues in the PI(4)P binding pocket.; T143, T148, the threonine residues that are phosphorylated by DNA-PK in human GOLPH3; LLDLD, the clathrin-binding motif. (C) Ribbon representation of the GOLPH3 protein structure (pdb: 3KN1, ref. [27]). The structure has been drawn in rainbow colors (from red: C-terminal residues, to violet: N-terminus of GOLPH3). α-helices are shown as spirals, while β-strands are indicated as arrows. The sulfate-binding pocket, indicating the putative site of PI(4)P binding, is pointed out by the black arrow. The red arrow indicates LLDLD residues of the putative clathrin-binding motif. The figure model was visualized using the Pymol software.

Figure 2. Schematic representation illustrating the main cellular functions of GOLPH3 protein

GOLPH3, by binding to PI(4)P-enriched Golgi membranes and to MYO18A protein, mediates a linkage with the F-actin cytoskeleton that provides the tensile force necessary for Golgi architecture and vesicle trafficking. Golgi dispersal, in response to DNA damage, depends on the GOLPH3-MYO18A-F-actin pathway and the DNA damage protein kinase (PK) that phosphorylates GOLPH3 on T143 and T148. Several vesicle trafficking routes depend on GOLPH3 function. Human GOLPH3 also localizes to mitochondria and regulates total mitochondrial mass through mitochondrial lipid biogenesis. GOLPH3 is required for anterograde vesicle trafficking from Golgi to plasma membrane. In addition this protein associates with Vps35 a subunit of the cargo-recognition complex of the retromer which regulates receptor recycling of several transmembrane receptors including receptor tyrosine kinases (RTKs). Thus GOLPH3 might function with Vps35 and the retromer to regulate receptor recycling of key surface signals and affect downstream mTOR signaling, a pathway that is also sensitive to mitochondrial dysfunction. GOLPH3 family proteins are also essential for normal glycosylation of glycoproteins at the Golgi, a process that has been associated with several biological processes that are relevant for cancer disease including cell migration and invasion, immune recognition and signal transduction. In this context, GOLPH3 regulates docking and localization of several Golgi-resident glycosyltransferases (GT).

Figure 3. A possible model illustrating GOLPH3 function during cytokinesis

Wild type function of the PI4KIIIβ (named Fwd in Drosophila) is required for PI(4)P synthesis at the Golgi. Recruitment of GOLPH3 to the Golgi depends on PI(4)P. Fwd protein binds Rab11 and recruits this protein on Golgi membranes. Wild type function of GOLPH3 is required to recruit PI(4)P-and Rab11-containing secretory organelles to the cleavage furrow. PI(4)P is the immediate precursor of PI(4,5)P2 that is generated in the cleavage furrow by PI(4)P 5-kinase. Binding to phosphatidic acid (PA), GOLPH3 might also contribute to PI(4)P 5-kinase activation and plasma membrane remodeling. PI(4)P-GOLPH3 and PI(4,5)P2 mediate the interaction of centralspindlin, septins and actomyosin with the plasma membrane at the cleavage site, playing a crucial role in contractile ring formation.