TY - JOUR
T1 - Midkine noncanonically suppresses AMPK activation through disrupting the LKB1-STRAD-Mo25 complex
AU - Xia, Tian
AU - Chen, Di
AU - Liu, Xiaolong
AU - Qi, Huan
AU - Wang, Wen
AU - Chen, Huan
AU - Ling, Ting
AU - Otkur, Wuxiyar
AU - Zhang, Chen Song
AU - Kim, Jongchan
AU - Lin, Sheng Cai
AU - Piao, Hai long
N1 - Publisher Copyright:
© 2022, The Author(s).
PY - 2022/4
Y1 - 2022/4
N2 - Midkine (MDK), a secreted growth factor, regulates signal transduction and cancer progression by interacting with receptors, and it can be internalized into the cytoplasm by endocytosis. However, its intracellular function and signaling regulation remain unclear. Here, we show that intracellular MDK interacts with LKB1 and STRAD to disrupt the LKB1-STRAD-Mo25 complex. Consequently, MDK decreases the activity of LKB1 to dampen both the basal and stress-induced activation of AMPK by glucose starvation or treatment of 2-DG. We also found that MDK accelerates cancer cell proliferation by inhibiting the activation of the LKB1-AMPK axis. In human cancers, compared to other well-known growth factors, MDK expression is most significantly upregulated in cancers, especially in liver, kidney and breast cancers, correlating with clinical outcomes and inversely correlating with phosphorylated AMPK levels. Our study elucidates an inhibitory mechanism for AMPK activation, which is mediated by the intracellular MDK through disrupting the LKB1-STRAD-Mo25 complex.
AB - Midkine (MDK), a secreted growth factor, regulates signal transduction and cancer progression by interacting with receptors, and it can be internalized into the cytoplasm by endocytosis. However, its intracellular function and signaling regulation remain unclear. Here, we show that intracellular MDK interacts with LKB1 and STRAD to disrupt the LKB1-STRAD-Mo25 complex. Consequently, MDK decreases the activity of LKB1 to dampen both the basal and stress-induced activation of AMPK by glucose starvation or treatment of 2-DG. We also found that MDK accelerates cancer cell proliferation by inhibiting the activation of the LKB1-AMPK axis. In human cancers, compared to other well-known growth factors, MDK expression is most significantly upregulated in cancers, especially in liver, kidney and breast cancers, correlating with clinical outcomes and inversely correlating with phosphorylated AMPK levels. Our study elucidates an inhibitory mechanism for AMPK activation, which is mediated by the intracellular MDK through disrupting the LKB1-STRAD-Mo25 complex.
UR - http://www.scopus.com/inward/record.url?scp=85128913418&partnerID=8YFLogxK
U2 - 10.1038/s41419-022-04801-0
DO - 10.1038/s41419-022-04801-0
M3 - 文章
C2 - 35487917
AN - SCOPUS:85128913418
SN - 2041-4889
VL - 13
JO - Cell Death and Disease
JF - Cell Death and Disease
IS - 4
M1 - 414
ER -
