title: MAP4K4 regulates integrin-FERM binding to control endothelial cell motility.
abstract: Cell migration is a stepwise process that coordinates multiple molecular machineries. Using in vitro angiogenesis screens with short interfering RNA and chemical inhibitors, we define here a MAP4K4-moesin-talin-β1-integrin molecular pathway that promotes efficient plasma membrane retraction during endothelial cell migration. Loss of MAP4K4 decreased membrane dynamics, slowed endothelial cell migration, and impaired angiogenesis in vitro and in vivo. In migrating endothelial cells, MAP4K4 phosphorylates moesin in retracting membranes at sites of focal adhesion disassembly. Epistasis analyses indicated that moesin functions downstream of MAP4K4 to inactivate integrin by competing with talin for binding to β1-integrin intracellular domain. Consequently, loss of moesin (encoded by the MSN gene) or MAP4K4 reduced adhesion disassembly rate in endothelial cells. Additionally, α5β1-integrin blockade reversed the membrane retraction defects associated with loss of Map4k4 in vitro and in vivo. Our study uncovers a novel aspect of endothelial cell migration. Finally, loss of MAP4K4 function suppressed pathological angiogenesis in disease models, identifying MAP4K4 as a potential therapeutic target.
authors: Molecular Biology Department, Genentech, Inc., South San Francisco, California 94080, USA.
authors: Philip
authors: P
authors: Vitorino
authors: Molecular Biology Department, Genentech, Inc., South San Francisco, California 94080, USA.
authors: Stacey
authors: S
authors: Yeung
authors: Molecular Biology Department, Genentech, Inc., South San Francisco, California 94080, USA.
authors: Ailey
authors: A
authors: Crow
authors: Chemical Biology and Therapeutics Department, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
authors: Jesse
authors: J
authors: Bakke
authors: Molecular Biology Department, Genentech, Inc., South San Francisco, California 94080, USA.
authors: Tanya
authors: T
authors: Smyczek
authors: Translational Oncology Department, Genentech, Inc., South San Francisco, California 94080, USA.
authors: Kristina
authors: K
authors: West
authors: Translational Oncology Department, Genentech, Inc., South San Francisco, California 94080, USA.
authors: Erin
authors: E
authors: McNamara
authors: Pathology Department, Genentech, Inc., South San Francisco, California 94080, USA.
authors: Jeffrey
authors: J
authors: Eastham-Anderson
authors: Translational Oncology Department, Genentech, Inc., South San Francisco, California 94080, USA.
authors: Stephen
authors: S
authors: Gould
authors: Structural Biology Department, Genentech, Inc., South San Francisco, California 94080, USA.
authors: Seth F
authors: SF
authors: Harris
authors: Discovery Chemistry Department, Genentech, Inc., South San Francisco, California 94080, USA.
authors: Chudi
authors: C
authors: Ndubaku
authors: Molecular Biology Department, Genentech, Inc., South San Francisco, California 94080, USA.
authors: Weilan
authors: W
authors: Ye
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002465:Cell Movement; D048430:Cell Shape / Q000187:drug effects; D042783:Endothelial Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D004843:Epistasis, Genetic; D022001:Focal Adhesions / Q000378:metabolism; D006801:Humans; D039423:Integrin alpha1 / Q000187:drug effects / Q000378:metabolism; D019012:Integrin beta1 / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D016023:Integrins / Q000187:drug effects / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008840:Microfilament Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D009389:Neovascularization, Pathologic; D010766:Phosphorylation; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D016608:Talin / Q000737:chemistry / Q000378:metabolism
chemical_list: D039423:Integrin alpha1; D019012:Integrin beta1; D016023:Integrins; D047908:Intracellular Signaling Peptides and Proteins; D008840:Microfilament Proteins; D016608:Talin; C071058:moesin; C117090:MAP4K4 protein, human; D017346:Protein Serine-Threonine Kinases