Tribbles homolog 2 (TRIB2) is functionally important for liver cancer cell survival and transformation. Our previous study demonstrates TRIB2 is stable in liver cancer cells due to the impaired ubiquitination by Smurf1. However, overexpression of Smurf1 alone cannot completely abolish TRIB2 protein expression, whether other potential factors involved in the degradation of TRIB2 still remains unclear. In the present study, we reveal that the stability and ubiquitination of TRIB2 can also be controlled by ubiquitin E3 ligase SCF beta-TRCP. Depletion of either Cullin1 or beta-TRCP up-regulates TRIB2 protein expression. Moreover, knockdown of beta-TRCP extends the half-life, whereas reduces ubiquitylation of TRIB2. Similar to Smurf1, beta-TRCP exerts its role through the TRIB2 Degradation Domain (TDD) at the N-terminus of the TRIB2 protein. Hence, we add TRIB2 to the substrate list of SCF beta-TRCP and the finding may be helpful in the treatment of TRIB2 dependent liver cancer. (C) 2013 Elsevier Inc. All rights reserved.