Functional analysis of Cullin 3 E3 ligases in tumorigenesis

Abstract

Cullin 3-RING ligases (CRL3) play pivotal roles in the regulation of various physiological and pathological processes, including neoplastic events. The substrate adaptors of CRL3 typically contain a BTB domain that mediates the interaction between Cullin 3 and target substrates to promote their ubiquitination and subsequent degradation. The biological implications of CRL3 adaptor proteins have been well described where they have been found to play a role as either an oncogene, tumor suppressor, or can mediate either of these effects in a context-dependent manner. Among the extensively studied CRL3-based E3 ligases, the role of the adaptor protein SPOP (speckle type BTB/POZ protein) in tumorigenesis appears to be tissue or cellular context dependent. Specifically, SPOP acts as a tumor suppressor via destabilizing downstream oncoproteins in many malignancies, especially in prostate cancer. However, SPOP has largely an oncogenic role in kidney cancer. Keap1, another well-characterized CRL3 adaptor protein, likely serves as a tumor suppressor within diverse malignancies, mainly due to its specific turnover of its downstream oncogenic substrate, NRF2 (nuclear factor erythroid 2-related factor 2). In accordance with the physiological role the various CRL3 adaptors exhibit, several pharmacological agents have been developed to disrupt its E3 ligase activity, therefore blocking its potential oncogenic activity to mitigate tumorigenesis.

KCTD: A new gene family involved in neurodevelopmental and neuropsychiatric disorders

“…The identification of BTB domains from other protein families as cullin‐binding partners by mass spectrometry, including several KCTD family members, fuels the search for biological roles for KCTD family proteins as exchangeable adaptors of cullin‐3‐RING E3 ubiquitin ligase complexes (CRLs). In this model, cullin‐3 interacts with the BTB domains of exchangeable adaptor proteins that serve to recruit different protein substrates for ubiquitination by the RBX‐RING protein bound to the C‐terminus of cullin‐3 (Figure ) . Thus, KCTD family proteins could function like a multihead screwdriver to recruit different cellular proteins for selective degradation by the proteasome or the lysosome to fine‐tune many cellular processes …”

Cullin‐3/KCTD10 E3 complex is essential for Rac1 activation through RhoB degradation in human epidermal growth factor receptor 2‐positive breast cancer cells

“…cell cycle progression, membrane trafficking, transcription, signaling in stress response, and cytoskeletal reorganization). Dysfunction of CUL3 has been implicated in the development of human diseases such as hypertension and cancer . CUL3 also regulates endothelial functions (e.g.…”

“…Dysfunction of CUL3 has been implicated in the development of human diseases such as hypertension and cancer. 3,4 CUL3 also regulates endothelial functions (e.g. cell proliferation and barrier function) and angiogenesis by formation of complexes with multiple BTBP.…”

RING finger protein 38 induces gastric cancer cell growth by decreasing the stability of the protein tyrosine phosphatase SHP‐1

“…The UPS is ATP-dependent and three classes of enzymes are required for mediating protein ubiquitination, including ubiquitin-activating enzyme E1, ubiquitinconjugating enzyme E2 and ubiquitin ligase E3 [20][21][22]. Among these, E3 ubiquitin ligases represent highly attractive protein targets for drug discovery, because the significance of E3 ligases as prospective targets for small molecule modulation is reinforced by ever growing evidences of their roles in tumors and other diseases [23,24].…”