The Molecular and Pathophysiological Functions of Members of the LNX/PDZRN E3 Ubiquitin Ligase Family

Abstract

The ligand of Numb protein-X (LNX) family, also known as the PDZRN family, is composed of four discrete RING-type E3 ubiquitin ligases (LNX1, LNX2, LNX3, and LNX4), and LNX5 which may not act as an E3 ubiquitin ligase owing to the lack of the RING domain. As the name implies, LNX1 and LNX2 were initially studied for exerting E3 ubiquitin ligase activity on their substrate Numb protein, whose stability was negatively regulated by LNX1 and LNX2 via the ubiquitin-proteasome pathway. LNX proteins may have versatile molecular, cellular, and developmental functions, considering the fact that besides these proteins, none of the E3 ubiquitin ligases have multiple PDZ (PSD95, DLGA, ZO-1) domains, which are regarded as important protein-interacting modules. Thus far, various proteins have been isolated as LNX-interacting proteins. Evidence from studies performed over the last two decades have suggested that members of the LNX family play various pathophysiological roles primarily by modulating the function of substrate proteins involved in several different intracellular or intercellular signaling cascades. As the binding partners of RING-type E3s, a large number of substrates of LNX proteins undergo degradation through ubiquitin-proteasome system (UPS) dependent or lysosomal pathways, potentially altering key signaling pathways. In this review, we highlight recent and relevant findings on the molecular and cellular functions of the members of the LNX family and discuss the role of the erroneous regulation of these proteins in disease progression.

Integrated analysis reveals potential significance of FKBP5 in the prognosis and immunity of osteoarthritis and pan-cancer

“…The results of ssGSEA showed a signi cant correlation between KLF9 and hypoxia and apoptosis; therefore, the mechanism of apoptosis induced by ROS in patients with OA and the potential role of KLF9 in this process need to be further investigated. PDZRN4, a member of the PDZRN family, is more likely to function as an E3 ubiquitin ligase because of its multiple PDZ and RING structural domains (53). Current studies suggest that it may act as a tumor suppressor in a variety of cancers (54)(55)(56).…”

High-Content RNAi Phenotypic Screening Unveils the Involvement of Human Ubiquitin-Related Enzymes in Late Cytokinesis

“…It should be noted that the lack of phenotypic effect observed with MIB1 could be due to the presence of several functional and redundant genes in mammalian cells. LNX2 is also known to target Numb for proteasomal degradation, hence influencing the Notch signaling in cis [ 58 , 59 ]. However, the role of Notch in cytokinesis has never been highlighted, despite clearly modulating the fate of daughter cells during asymmetric division [ 60 ].…”

“…It is possible that CEP55 is not recruited to the midbody because of its disorganisation, probably concomitant with the degradation of its protein components. LNX1 and LNX2 are structurally similar and display common protein substrates for ubiquitination [ 59 , 63 , 65 ]. Recently, proteomic studies have evidenced their potential substrates such as MID1 and MID2, as well as KIF14 [ 66 ].…”

LNX1 Contributes to Cell Cycle Progression and Cisplatin Resistance

“…LNX1 related protein, LNX2 is also reported to upregulate Wnt/beta-catenin pathway in colorectal cancers [13]. In addition, recent studies also showed the role of LNX1 in the nervous system and pathophysiological cell signaling [14,15].…”