RHOBTB2, like the other RHOBTB family member, RHOBTB1, and the divergent RHOBTB3 which does not belong to the RHO superfamily, binds CUL3 (cullin-3) (Berthold et al. 2008), a core component of BTB-CUL3-RBX1 E3 ubiquitin ligase complexes. Binding of GTP to RHOBTB2, facilitated by the HSP90 chaperone complex, enables binding of RHOBTB2 to CUL3 (Manjarrez et al. 2014). RHOBTB2 is thought to act as the regulatory BTB component of the BTB-CUL3-RBX1 complex by recruiting target proteins for ubiquitination and subsequent proteasome-mediated degradation (Wilkins et al. 2004). RHOBTB2 is a substrate adaptor for Musashi 2 (MSI2), targeting it to CUL3 complexes for ubiquitination and proteasomal degradation, thus suppressing tumorigenesis (Choi et al. 2017).

The following candidate RHOBTB2 interactors have been discovered in the high throughput screen by Bagci et al. 2020:
ACTG1 (Bagci et al. 2020)
ACTN1 (Bagci et al. 2020)
CCT2 (Bagci et al. 2020)
CCT6A (Bagci et al. 2020)
CCT7 (Bagci et al. 2020)
DBN1 (Bagci et al. 2020)
DDX39B (Bagci et al. 2020)
HNRNPC (Bagci et al. 2020)
MYO6 (Bagci et al. 2020)
PHIP (Bagci et al. 2020)
RBMX (Bagci et al. 2020)
SRRM1 (Bagci et al. 2020)
STK38 (Bagci et al. 2020)
TMOD3 (Bagci et al. 2020)
TRA2B (Bagci et al. 2020)
TWF1 (Bagci et al. 2020)
TXNL1 (Bagci et al. 2020).
Some of these interactors are part of the CCT chaperone complex (CCT2, CCT6A and CCT7), some are related to the actin cytoskeleton (ACTG1, ACTN1, DBN1, MYO6, TMOD3 and TWF1), or RNA splicing and export (DDX39B, HNRNPC, RBMX and SRRM1).