Our research lies in the broad area of the molecular mechanisms that underlie metabolic homeostasis and its relationship to cell growth control. We have discovered a signaling pathway comprising the protein kinase GSK3, acetyltransferase TIP60, and protein kinase ULK1, which activates autophagy in cells deprived of serum, elucidating the molecular mechanism linking nutritional starvation to autophagy. We have also revealed that the ULK kinases phosphorylate multiple glycolytic enzymes and regulate glucose metabolic fluxes dependently of autophagy. 

    The main focus of our research has also been on the mechanisms for the regulation of the AMP-activated protein kinase. We have shown that the lowenergy signal AMP can autonomously initiate assembly of an activating complex for the energy sensor kinase AMPK, in that the scaffold protein AXIN tethers LKB1 to AMPK. Moreover, we have found that the AXIN/LKB1/AMPK complex and mTORC1 inversely utilize the common v-ATPaseRagulator complex for activation on the surface of lysosome, thereby uncovering a switch between anabolism and catabolism. We are exploring further how AMPK and its activating kinase LKB1 are regulated and the biological functions of these kinases. 

1.     Gonzalez A, Hall MD, Lin SC, Hardie DG*. AMPK and TOR: The yin and yang of cellular nutrient sensing and growth control. Cell Metabolism 2020;31 (3): 472-492. (Review)

2.      Zhang CS, Hardie DG*, Lin SC*. Glucose starvation blocks translation at multiple levels. Cell Metabolism 2020; 31 (2): 217-218.

3.      Li M^#, Zhang CS^#, Zong Y^#, Feng JW, Ma T, Hu M, Lin Z, Li X, Xie C, Wu Y, Jiang D, Li Y, Zhang C, Tian X, Wang W, Yang Y, Chen J, Cui J, Wu YQ, Chen X, Liu QF, Wu J, Lin SY, Ye Z, Liu Y, Piao HL, Yu L, Zhou Z, Xie XS, Hardie DG, Lin SC*. Transient receptor potential channels are essential for glucose sensing by aldolase and AMPK. Cell Metabolism 2019; 30 (3): 508–524.

4.     Zong Y^#, Zhang CS^#, Li M^#, Wang W^#, Wang Z, Hawley SA, Ma T, Feng JW, Tian X, Qi Q, Wu YQ, Zhang C, Ye Z, Lin SY, Piao HL, Hardie DG, Lin SC*.Hierarchical activation of compartmentalized pools of AMPK depends on severity of nutrient or energy stress. Cell Research 2019; 29 (6): 460-473.

5.      Lin SY, Zhang CS, Lin SC*. Carbohydrates: Not ALL that Bad? Cell Metabolism 2018; 28 (5): 671-672.

6.    Cai WF, Zhang C, Wu YQ, Zhuang G, Ye Z, Zhang CS*, Lin SC*. Glutaminase GLS1 senses glutamine in a nonenzymatic manner triggering mitochondrial fusion. Cell Research 2018; 28 (8): 865–867.

7.      Lin SC*, Hardie DG*. AMPK: Sensing Glucose as well as Cellular Energy Status. Cell Metabolism 2018; 27 (2): 299-313. (Invited Review)

8.     Luo H^#, Jiang M^#, Lian G, Liu Q, Shi M, Li TY, Song L, Ye J, He Y, Yao L, Zhang C, Lin ZZ, Zhang CS, Zhao TJ, Jia WP, Li P, Lin SY*, Lin SC*. Aida Mediates ERAD to Selectively Downregulate Triacylglycerol Synthesis Enzymes and Prevent Obesity. Cell Metabolism 2018; 27 (4): 843-853.

9.      Li TY^#, Song L^#, Sun Y^#, Li J, Yi C, Lam SM, Xu D, Zhou L, Li X, Yang Y, Zhang CS, Xie C, Huang X, Shui G, Lin SY, Reue K, Lin SC*. Tip60-mediated lipin 1 acetylation and ER translocation determine triacylglycerol synthesis rate. NatureCommunications 2018; 9 (1): 1916.

10.   Hardie DG*, Lin SC. AMP-activated protein kinase – not just an energy sensor [version 1; referees: 3 approved]. F1000Research 2017; 6 (F1000 Faculty Rev): 1724. (Review)

11.   Zhang CS^#, Hawley SA^#, Zong Y^#, Li M^#, Wang Z, Gray A, Ma T, Cui J, Feng JW, Zhu M, Wu YQ, Li TY, Ye Z, Lin SY, Yin H, Piao HL, Hardie DG*, Lin SC*. Fructose-1,6-bisphosphate and aldolase mediate glucose sensing by AMPK. Nature 2017; 548 (7665): 112-116.

12. Zhang CS, Lin SC*. AMPK Promotes Mitophagy through Facilitating Mitochondrial Fission. Cell Metabolism 2016; 23 (3): 399-341.

13.  Zhang CS^#, Li M^#, Ma T^#, Zong Y, Cui J, Feng JW, Wu YQ, Lin SY, Lin SC*. Metformin activates AMPK through the lysosomal pathway. Cell Metabolism 2016; 24 (4): 521-522.

14.   Li TY, Liang Y, Sun Y, Liang Y, Liu Q, Shi YZ, Zhang SC, Zhang CX, Song LT, Zhang P, Zhang XZ, Li XT, Chen T, Huang HY, He XD, Wang Y, Wu YQ, Chen SX, Jiang M, Chen CH, Xie CC, Yang JY, Lin Y, Zhao SM, Ye ZY, Lin SY, Chiu DT, Lin SC*. ULK1/2 Constitute a Bifurcate Node Controlling Glucose Metabolic Fluxes in addition to Autophagy. Molecular Cell 2016; 62 (3): 359-370.

15.   Zhang CS^#, Liu Q^#, Li M^#, Lin SY^#, Peng Y, Wu D, Li TY, Fu Q, Jia W, Wang X, Ma T, Zong Y, Cui J, Pu C, Lian G, Guo H, Ye Z, Lin SC*. RHOBTB3 promotes proteasomal degradation of HIF1alpha through facilitating hydroxylation and suppresses the Warburg effect. Cell Research 2015; 25 (9): 1025-1042.

16.   Zhang CS^#, Jiang B^#, Li M^#, Zhu M, Peng Y, Zhang YL, Wu YQ, Li TY, Liang Y, Lu Z, Lian G, Liu Q, Guo H, Yin Z, Ye Z, Han J, Wu JW, Yin H, Lin SY, Lin SC*. The Lysosomal v-ATPase-Ragulator Complex is a common activator for AMPK and mTORC1, acting as a switch between catabolism and anabolism. Cell Metabolism 2014; 20 (3): 526-540.

17.   Zhang YL^#, Guo H^#, Zhang CS^#, Lin SY, Yin Z, Peng Y, Luo H, Shi Y, Lian G, Zhang C, Li M, Ye Z, Ye J, Han J, Li P, Wu JW, Lin SC*. AMP as a low energy charge signal autonomously initiates assembly of AXIN-AMPK-LKB1 complex for AMPK activation. Cell Metabolism 2013; 18 (4): 546-555.

18.  Guo HL^#, Zhang C^#, Liu Q^#, Li Q, Lian G, Wu D, Li X, Zhang W, Shen Y, Ye Z, Lin SY, Lin SC*. The Axin/TNKS complex interacts with KIF3A and is required for insulin-stimulated GLUT4 translocation. Cell Research 2012; 22 (8): 1246-1257.

19.   Lin SY^#, Li TY^#, Liu Q, Zhang C, Li X, Chen Y, Zhang SM, Lian G, Liu Q, Ruan K, Wang Z, Zhang CS, Chien KY, Wu J, Li Q, Han J, Lin SC*. GSK3-TIP60-ULK1 signaling pathway links growth factor deprivation to autophagy. Science 2012; 336 (6080): 477-481.

20.   Li Q^#, Lin SY^#, Wang X^#, Lian G, Lu Z, Guo H, Ruan K, Wang Y, Ye Z, Han J, Lin SC*. Axin determines cell fate by controlling the p53 activation threshold after DNA damage. Nature Cell Biology 2009; 11 (9): 1128-1135.