title: ZF21 protein, a regulator of the disassembly of focal adhesions and cancer metastasis, contains a novel noncanonical pleckstrin homology domain.
abstract: Directional migration of adherent cells on an extracellular matrix requires repeated formation and disassembly of focal adhesions (FAs). Directional migration of adherent cells We have identified ZF21 as a regulator of disassembly of FAs and cell migration, and increased expression of the gene has been linked to metastatic colon cancer. ZF21 is a member of a protein family characterized by the presence of the FYVE domain, which is conserved among Fab1p, YOPB, Vps27p, and EEA1 proteins, and has been shown to mediate the binding of such proteins to phosphoinositides in the lipid layers of cell membranes. ZF21 binds multiple factors that promote disassembly of FAs such as FAK, β-tubulin, m-calpain, and SHP-2. ZF21 does not contain any other known protein motifs other than the FYVE domain, but a region of the protein C-terminal to the FYVE domain is sufficient to mediate binding to β-tubulin. In this study, we demonstrate that the C-terminal region is important for the ability of ZF21 to induce disassembly of FAs and cell migration, and to promote an early step of experimental metastasis to the lung in mice. In light of the importance of the C-terminal region, we analyzed its ternary structure using NMR spectroscopy. We demonstrate that this region exhibits a structure similar to that of a canonical pleckstrin homology domain, but that it lacks a positively charged interface to bind phosphatidylinositol phosphate. Thus, ZF21 contains a novel noncanonical PH-like domain that is a possible target to develop a therapeutic strategy to treat metastatic cancer.
authors.affiliation: Division of Cancer Cell Research, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo, 108-8639, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Nagano
authors.forename: Daisuke
authors.initials: D
authors.lastname: Hoshino
authors.forename: Seizo
authors.initials: S
authors.lastname: Koshiba
authors.forename: Takuya
authors.initials: T
authors.lastname: Shuo
authors.forename: Naohiko
authors.initials: N
authors.lastname: Koshikawa
authors.forename: Tadashi
authors.initials: T
authors.lastname: Tomizawa
authors.forename: Fumiaki
authors.initials: F
authors.lastname: Hayashi
authors.forename: Naoya
authors.initials: N
authors.lastname: Tochio
authors.forename: Takushi
authors.initials: T
authors.lastname: Harada
authors.forename: Toshifumi
authors.initials: T
authors.lastname: Akizawa
authors.forename: Satoru
authors.initials: S
authors.lastname: Watanabe
authors.forename: Noriko
authors.initials: N
authors.lastname: Handa
authors.forename: Mikako
authors.initials: M
authors.lastname: Shirouzu
authors.forename: Takanori
authors.initials: T
authors.lastname: Kigawa
authors.forename: Shigeyuki
authors.initials: S
authors.lastname: Yokoyama
authors.forename: Motoharu
authors.initials: M
authors.lastname: Seiki
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D002154:Calpain / Q000378:metabolism; D002352:Carrier Proteins / Q000737:chemistry / Q000502:physiology*; D002460:Cell Line; D002465:Cell Movement; D051417:Focal Adhesion Kinase 1 / Q000378:metabolism; D022001:Focal Adhesions / Q000473:pathology*; D006801:Humans; D019012:Integrin beta1 / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D051379:Mice; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000473:pathology*; D010766:Phosphorylation; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D019012:Integrin beta1; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C568304:ZF21 protein, mouse; C557458:ZFYVE21 protein, human; D051417:Focal Adhesion Kinase 1; D017027:Protein Tyrosine Phosphatases; D002154:Calpain