Proteomics Identifies Golgi phosphoprotein 3 (GOLPH3) with A Link Between Golgi Structure, Cancer, DNA Damage and Protection from Cell Death

Abstract

GOLPH3 is the first example of a Golgi resident oncogene protein. It was independently identified in multiple screens; first in proteomic-based screens as a resident protein of the Golgi apparatus, and second as an oncogene product in a screen for genes amplified in cancer. A third screen uncovered the association of GOLPH3 with the Golgi resident phospholipid, phosphatidyl inositol 4 phosphate (PI4P) to maintain the characteristic ribbon structure of the Golgi apparatus favoring vesicular transport of secretory proteins.

Fig. 1.

Characterization and localization of GOLPH3. A, Morphometric grid used for quantification of Golgi apparatus in isolated Golgi fractions of the liver as performed by Bell et al. (6). Most profiles from n = 3 Golgi fractions (84%) are of stacked Golgi cisternae (e.g. G) with endoplasmic reticulum (ER), mitochondrial (mit), and peroxisomal (p) contaminants indicated. B, Primary sequence of human GOLPH3 with the tryptic peptide characterized by tandem mass spectrometry. C, EM of cryosections of isolated Golgi labeled with gold decorated antibodies to monospecific anti-GOLPH3. Gold particles (indicated by arrowheads) are at the periphery of stacked Golgi cisternae. The cis and trans side of the stacked Golgi cisternae are indicated. Modified from (6).

Fig. 2.

Homology of GOLPH3 structure with Vps74p showing the lipid-binding pocket of each (in lower boxes). Taken from (21) with permission from the Journal of Cell Biology. (©2009 Woods et al. Journal of Cell Biology. 187:967–75. doi: 10.1083/jcb.200909063.)

Fig. 3.

Left side, Illustration of a Golgi ribbon with PI4P and GOLPH3 during normal secretion. The Golgi is formed of adjacent stacks of cisternae whose edges are connected by tubules. Right side, DNA damage induced activation of DNA PK, the proposed phosphorylation of GOLPH3, the scission of the Golgi ribbon at the level of the interconnecting tubules resulting in a reduction of secretion.