Oncogenic B-RAF negatively regulates the tumor suppressor LKB1 to promote melanoma cell proliferation.
The LKB1-AMPK signaling pathway serves as a critical cellular sensor coupling energy homeostasis to cell growth, proliferation, and survival. However, how tumor cells suppress this signaling pathway to gain growth advantage under conditions of energy stress is largely unknown. Here, we show that AMPK activation is suppressed in melanoma cells with the B-RAF V600E mutation and that downregulation of B-RAF signaling activates AMPK. We find that in these cells LKB1 is phosphorylated by ERK and Rsk, two kinases downstream of B-RAF, and that this phosphorylation compromises the ability of LKB1 to bind and activate AMPK. Furthermore, expression of a phosphorylation-deficient mutant of LKB1 allows activation of AMPK and inhibits melanoma cell proliferation and anchorage-independent cell growth. Our findings provide a molecular linkage between the LKB1-AMPK and the RAF-MEK-ERK pathways and suggest that suppression of LKB1 function by B-RAF V600E plays an important role in B-RAF V600E-driven tumorigenesis.
Zheng
Bin
B
Division of Signal Transduction, Beth Israel Deaconess Medical Center, Boston, MA 02115, USA. bzheng@bidmc.harvard.edu
Jeong
Joseph H
JH
Asara
John M
JM
Yuan
Yuan-Ying
YY
Granter
Scott R
SR
Chin
Lynda
L
Cantley
Lewis C
LC
D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000818:Animals; D019556:COS Cells; D049109:Cell Proliferation; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D006367:HeLa Cells; D006801:Humans; D008545:Melanoma / Q000201:enzymology* / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
D017346:Protein Serine-Threonine Kinases; D048493:Proto-Oncogene Proteins B-raf; C109790:STK11 protein, human; D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases