Midkine noncanonically suppresses AMPK activation through disrupting the LKB1-STRAD-Mo25 complex.
Tian XiaDi ChenXiaolong LiuHuan QiWen WangHuan ChenTing LingWuxiyar OtkurChen-Song ZhangJongchan KimSheng-Cai LinHai-Long PiaoPublished in: Cell death & disease (2022)
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.
Keyphrases
- growth factor
- skeletal muscle
- stress induced
- protein kinase
- cell proliferation
- papillary thyroid
- signaling pathway
- poor prognosis
- endothelial cells
- squamous cell
- reactive oxygen species
- squamous cell carcinoma
- blood pressure
- cell cycle
- metabolic syndrome
- adipose tissue
- induced pluripotent stem cells
- long non coding rna
- blood glucose
- insulin resistance
- combination therapy
- weight loss