UCSF

Pseudokinases comprise approximately 10% of the human kinome and despite lacking catalytic activity, play essential roles in cell signaling by functioning as scaffolds, competitive inhibitors, or allosteric regulators of their binding partners. Tribbles 2 (TRIB2) is a pseudokinase scaffold protein that is frequently overexpressed in cancer, including melanoma. TRIB2 has been implicated in the regulation of the MAPK and PI3K-Akt-mTOR signaling pathway, however, how it does so mechanistically and the functional consequences of this regulation are not fully understood. In our work, we investigate the role of TRIB2 in melanoma and show that TRIB2 contributes to key features of malignancy, including altered cell and nuclear morphology and proliferation. We describe a novel interaction between TRIB2 and the mTORC1 adaptor Raptor that inhibits mTORC1-p70S6K signaling and establishes TRIB2 as a negative regulator of this cell growth-promoting pathway. We further show that TRIB2 undergoes proteasome-dependent degradation upon inhibition of MAPK signaling in melanoma cells. Collectively, we highlight TRIB2 as a regulator that both shapes and is shaped by MAPK and PI3K-Akt-mTOR signaling in melanoma. These findings position TRIB2 at the intersection of two of the most frequently dysregulated pathways in cancer, highlighting its regulation as a potential therapeutic target.