TrCP2

TrCP2, also known as beta-TrCP2 or FBXW11, is a human F-box WD40-repeat protein that functions as a substrate recognition component of the SCF (Skp1-Cullin1-F-box) E3 ubiquitin ligase complex. It is one of two paralogs of beta-TrCP, the other being TrCP1 (FBXW11 is the gene name sometimes confused; in practice TrCP2 is FBXW11). TrCP2 participates in tagging a broad set of phosphorylated proteins with ubiquitin, marking them for proteasomal degradation and thereby regulating diverse cellular processes.

Structurally, TrCP2 contains an N-terminal F-box domain that binds Skp1, linking the protein to the SCF core, and C-terminal WD40 repeats that form a beta-propeller for substrate binding. Substrate recognition typically relies on a phosphodegron motif, commonly a DSGXXS or similar sequence that becomes phosphorylated by kinases such as CK1 and GSK3. Phosphorylation creates a binding site for the WD40 domain, enabling ubiquitination by the SCF complex.

TrCP2 regulates multiple signaling pathways by controlling stability of substrates. Notable targets include IκBα, whose degradation activates NF-κB signaling; β-catenin, a key effector of the Wnt pathway; and cell cycle regulators such as Emi1, Cdt1, Claspin, and Wee1. Through these actions, TrCP2 influences inflammation, development, DNA replication licensing, and cell cycle progression.

Dysregulation of TrCP2 activity or expression has been linked to disease processes, including cancer and inflammatory disorders, reflecting its central role in ubiquitin-mediated proteolysis. TrCP2 operates in concert with TrCP1, and together they provide redundant and context-dependent regulation of numerous substrates across tissues and cellular states.