title: GOLPH3 drives cell migration by promoting Golgi reorientation and directional trafficking to the leading edge.
abstract: The mechanism of directional cell migration remains an important problem, with relevance to cancer invasion and metastasis. GOLPH3 is a common oncogenic driver of human cancers, and is the first oncogene that functions at the Golgi in trafficking to the plasma membrane. Overexpression of GOLPH3 is reported to drive enhanced cell migration. Here we show that the phosphatidylinositol-4-phosphate/GOLPH3/myosin 18A/F-actin pathway that is critical for Golgi-to-plasma membrane trafficking is necessary and limiting for directional cell migration. By linking the Golgi to the actin cytoskeleton, GOLPH3 promotes reorientation of the Golgi toward the leading edge. GOLPH3 also promotes reorientation of lysosomes (but not other organelles) toward the leading edge. However, lysosome function is dispensable for migration and the GOLPH3 dependence of lysosome movement is indirect, via GOLPH3's effect on the Golgi. By driving reorientation of the Golgi to the leading edge and driving forward trafficking, particularly to the leading edge, overexpression of GOLPH3 drives trafficking to the leading edge of the cell, which is functionally important for directional cell migration. Our identification of a novel pathway for Golgi reorientation controlled by GOLPH3 provides new insight into the mechanism of directional cell migration with important implications for understanding GOLPH3's role in cancer.
authors.affiliation: Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Diego, La Jolla, CA 92093.
authors.forename: Mengke
authors.initials: M
authors.lastname: Xing
authors.affiliation: Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Diego, La Jolla, CA 92093.
authors.forename: Marshall C
authors.initials: MC
authors.lastname: Peterman
authors.affiliation: Small Molecule Discovery Program, Ludwig Institute for Cancer Research, La Jolla, CA 92093.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Davis
authors.affiliation: Department of Cellular and Molecular Medicine, Ludwig Institute for Cancer Research, University of California, San Diego, La Jolla, CA 92093.
authors.forename: Karen
authors.initials: K
authors.lastname: Oegema
authors.affiliation: Small Molecule Discovery Program, Ludwig Institute for Cancer Research, La Jolla, CA 92093.
authors.forename: Andrew K
authors.initials: AK
authors.lastname: Shiau
authors.affiliation: Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Diego, La Jolla, CA 92093 sjfield@ucsd.edu.
authors.forename: Seth J
authors.initials: SJ
authors.lastname: Field
mesh_terms: D000199:Actins / Q000378:metabolism; D000595:Amino Acid Sequence; D018929:Cell Culture Techniques; D002462:Cell Membrane / Q000378:metabolism; D002465:Cell Movement / Q000502:physiology; D016764:Cell Polarity; D003599:Cytoskeleton; D006056:Golgi Apparatus / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism* / Q000502:physiology; D009218:Myosins / Q000378:metabolism; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism; D021381:Protein Transport / Q000502:physiology; D015398:Signal Transduction
chemical_list: D000199:Actins; D008565:Membrane Proteins; D009218:Myosins; D018129:Phosphatidylinositol Phosphates; C429024:GOLPH3 protein, human; C037178:phosphatidylinositol 4-phosphate; C407152:MYO18A protein, human