4.4 Article

Adaptor Protein2 ( AP2) Orchestrates CXCR2-Mediated Cell Migration

期刊

TRAFFIC
卷 15, 期 4, 页码 451-469

出版社

WILEY
DOI: 10.1111/tra.12154

关键词

AP2; AP2-2; AP2-sigma 2; chemotaxis; CXCR2; internalization; PIP2 patches

资金

  1. NIH [CA-34590, T32 119925, F32 CA171895]
  2. Tennessee Valley Healthcare System
  3. Department of Veterans Affairs, Vanderbilt Ingram Cancer Center Support grant [CA68485]
  4. Ingram Professorship
  5. VA Merit Award

向作者/读者索取更多资源

The chemokine receptor CXCR2 is vital for inflammation, wound healing, angiogenesis, cancer progression and metastasis. Adaptor protein 2 (AP2), a clathrin binding heterotetrameric protein comprised of , 2, 2 and sigma 2 subunits, facilitates clathrin-mediated endocytosis. Mutation of the LLKIL motif in the CXCR2 carboxyl-terminal domain (CTD) results in loss of AP2 binding to the receptor and loss of ligand-mediated receptor internalization and chemotaxis. AP2 knockdown also results in diminished ligand-mediated CXCR2 internalization, polarization and chemotaxis. Using knockdown/rescue approaches with AP2-2 mutants, the binding domains were characterized in reference to CXCR2 internalization and chemotaxis. When in an open conformation, 2 Patch 1 and Patch 2 domains bind tightly to membrane PIP2 phospholipids. When AP2-2, is replaced with 2 mutated in Patch 1 and/or Patch 2 domains, ligand-mediated receptor binding and internalization are not lost. However, chemotaxis requires AP2-2 Patch 1, but not Patch 2. AP2-sigma 2 has been demonstrated to bind dileucine motifs to facilitate internalization. Expression of AP2-sigma 2 V88D and V98S dominant negative mutants resulted in loss of CXCR2 mediated chemotaxis. Thus, AP2 binding to both membrane phosphatidylinositol phospholipids and dileucine motifs is crucial for directional migration or chemotaxis. Moreover, AP2-mediated receptor internalization can be dissociated from AP2-mediated chemotaxis.

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