title: Microtubules regulate focal adhesion dynamics through MAP4K4.
abstract: Disassembly of focal adhesions (FAs) allows cell retraction and integrin detachment from the extracellular matrix, processes critical for cell movement. Growth of microtubules (MTs) can promote FA turnover by serving as tracks to deliver proteins essential for FA disassembly. The molecular nature of this FA "disassembly factor," however, remains elusive. By quantitative proteomics, we identified mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4) as an FA regulator that associates with MTs. Knockout of MAP4K4 stabilizes FAs and impairs cell migration. By exploring underlying mechanisms, we further show that MAP4K4 associates with ending binding 2 (EB2) and IQ motif and SEC7 domain-containing protein 1 (IQSEC1), a guanine nucleotide exchange factor specific for Arf6, whose activation promotes integrin internalization. Together, our findings provide critical insight into FA disassembly, suggesting that MTs can deliver MAP4K4 toward FAs through EB2, where MAP4K4 can, in turn, activate Arf6 via IQSEC1 and enhance FA dissolution.
authors.affiliation: Ben May Department for Cancer Research, The University of Chicago, Chicago, IL 60637, USA.
authors.forename: Jiping
authors.initials: J
authors.lastname: Yue
authors.affiliation: Division of Cardiology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Min
authors.initials: M
authors.lastname: Xie
authors.affiliation: Ben May Department for Cancer Research, The University of Chicago, Chicago, IL 60637, USA.
authors.forename: Xuewen
authors.initials: X
authors.lastname: Gou
authors.affiliation: Ben May Department for Cancer Research, The University of Chicago, Chicago, IL 60637, USA.
authors.forename: Philbert
authors.initials: P
authors.lastname: Lee
authors.affiliation: British Heart Foundation Centre of Research Excellence, Imperial College London, Sir Alexander Fleming Building, Room 258, London W12 ONN, UK.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Schneider
authors.affiliation: Ben May Department for Cancer Research, The University of Chicago, Chicago, IL 60637, USA. Electronic address: xiaoyangwu@uchicago.edu.
authors.forename: Xiaoyang
authors.initials: X
authors.lastname: Wu
mesh_terms: D000818:Animals; D002448:Cell Adhesion / Q000502:physiology; D002465:Cell Movement / Q000502:physiology; D002478:Cells, Cultured; D005109:Extracellular Matrix / Q000378:metabolism; D022001:Focal Adhesions / Q000378:metabolism*; D016023:Integrins / Q000378:metabolism; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D051379:Mice; D008870:Microtubules / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D000097782:NF-kappaB-Inducing Kinase
chemical_list: D016023:Integrins; D020930:MAP Kinase Kinase Kinases; D017346:Protein Serine-Threonine Kinases; D000097782:NF-kappaB-Inducing Kinase