My research is to understand molecular mechanisms that govern the biological functions of the intracellular signaling network in both physiological and pathological events. We focus on regulation of JNK, which is member of the mitogen-activated protein kinase (MAPK) superfamily. JNK is activated by a MAP kinase module through sequential protein phosphorylation in response to a variety of extracellular stimuli, including proto-oncogens, growth factors, inflammatory cytokines, and physical stresses. Once activated, JNK phosphorylates its cytoplasmic target proteins such as members of the Bcl-2 family proteins, Itch, tau, IRS-1, or its nuclear target proteins such as the transcription factors c-Jun, ATF2, Elk-1, Stat3 and p53, thereby controlling proliferation, differentiation, programmed death and transformation. Not surprisingly, JNK is involved in the process of many human diseases including lung diseases and lung cancer. Through its involvement in regulation of airway smooth muscle cell proliferation, cell death, myofibroblasts proliferation, cytokine synthesis and transformation, JNK is likely to play a critical role in asthma, ischemia/reperfusion damage, pulmonary fibrosis, allergic inflammation in lung and NSCLC. However, the challenge is how to selectively modulate JNK activity in vivo.
We have evidence that JNK functions as a protein complex, i.e., the JNK signalsome that is composed of both known JNK activators and novel stimulus-dependent modulators or regulators (SMOR). SMORs are selectively recruited to or dissociated from the JNK signalsome in a stimulus-dependent manner, thereby specifying the activation of JNK by various extracellular stimuli. It is possible that one can target a unique SMOR to selectively regulate JNK activation by a specific stimulus without affecting JNK activation by other stimuli or affecting activation of other singling pathways by that stimulus. Our study on the JNK signalsome should shed light on our understanding of the molecular mechanism of pulmonary diseases including lung cancer and provide potential therapeutic targets.
Publications:
Liu J and Lin A. (2007). Integration of JNK and NF-kB signaling in human disease. Oncogene 26:3267-3278.
Liu J, Yang D, Minemoto Y, Leitges M, Rosner MR, and Lin A. (2006). NF-kB is required for UV-induced JNK activation via induction of PKCd. Molecular Cell 21(4):467-80.
Liu J, Minemoto Y, and Lin A. (2004). JNK1, but not JNK2, is essential for TNF-a- induced c-Jun kinase activation and apoptosis. Molecular and Cellular Biology 24(24):10844-56.
Yu C,a Minemoto Y,a Zhang J,a Liu J,a Tang F, Bui T, Xiang J, and Lin A. (2004). JNK Suppresses Apoptosis via Phosphorylation of the Proapoptotic Bcl-2 Family Protein BAD. Molecular Cell 13(3):329-40. a. These authors contribute equally to the work.
