AMP-activated protein kinase fortifies epithelial tight junctions during energetic stress via its effector GIV/Girdin.
Loss of epithelial polarity impacts organ development and function; it is also oncogenic. AMPK, a key sensor of metabolic stress stabilizes cell-cell junctions and maintains epithelial polarity; its activation by Metformin protects the epithelial barrier against stress and suppresses tumorigenesis. How AMPK protects the epithelium remains unknown. Here, we identify GIV/Girdin as a novel effector of AMPK, whose phosphorylation at a single site is both necessary and sufficient for strengthening mammalian epithelial tight junctions and preserving cell polarity and barrier function in the face of energetic stress. Expression of an oncogenic mutant of GIV (cataloged in TCGA) that cannot be phosphorylated by AMPK increased anchorage-independent growth of tumor cells and helped these cells to evade the tumor-suppressive action of Metformin. This work defines a fundamental homeostatic mechanism by which the AMPK-GIV axis reinforces cell junctions against stress-induced collapse and also provides mechanistic insight into the tumor-suppressive action of Metformin.
Department of Medicine, University of California, San Diego, San Diego, United States.
Nicolas
N
Aznar
Department of Medicine, University of California, San Diego, San Diego, United States.
Arjun
A
Patel
Department of Medicine, University of California, San Diego, San Diego, United States.
Cristina C
CC
Rohena
Department of Medicine, University of California, San Diego, San Diego, United States.
Ying
Y
Dunkel
Department of Medicine, University of California, San Diego, San Diego, United States.
Linda P
LP
Joosen
Department of Cellular and Molecular Medicine, University of California, San Diego, San Diego, United States.
Vanessa
V
Taupin
Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, San Diego, United States.
Irina
I
Kufareva
Department of Cellular and Molecular Medicine, University of California, San Diego, San Diego, United States.
Marilyn G
MG
Farquhar
Department of Medicine, University of California, San Diego, San Diego, United States.|Department of Cellular and Molecular Medicine, University of California, San Diego, San Diego, United States.|Moores Cancer Center, University of California, San Diego, San Diego, United States.
Pradipta
0000-0002-8917-3201
P
Ghosh
D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D006801:Humans; D008840:Microfilament Proteins / Q000378:metabolism*; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D019108:Tight Junctions / Q000502:physiology*; D033921:Vesicular Transport Proteins / Q000378:metabolism*
C502451:CCDC88A protein, human; D008840:Microfilament Proteins; D033921:Vesicular Transport Proteins; D055372:AMP-Activated Protein Kinases
Colon cancer; Metformin, AMPK; cancer biology; ccdc88a/GIRDIN; cell biology; energetic stress; epithelial cell polarity; human; tight junctions