E3 ubiquitin ligase Casitas B lineage lymphoma-b and its potential therapeutic implications for immunotherapy

Abstract

Summary The distinction of self from non‐self is crucial to prevent autoreactivity and ensure protection from infectious agents and tumors. Maintaining the balance between immunity and tolerance of immune cells is strongly controlled by several sophisticated regulatory mechanisms of the immune system. Among these, the E3 ligase ubiquitin Casitas B cell lymphoma‐b (Cbl‐b) is a newly identified component in the ubiquitin‐dependent protein degradation system, which is thought to be an important negative regulator of immune cells. An update on the current knowledge and new concepts of the relevant immune homeostasis program co‐ordinated by Cbl‐b in different cell populations could pave the way for future immunomodulatory therapies of various diseases, such as autoimmune and allergic diseases, infections, cancers and other immunopathological conditions. In the present review, the latest findings are comprehensively summarized on the molecular structural basis of Cbl‐b and the suppressive signaling mechanisms of Cbl‐b in physiological and pathological immune responses, as well as its emerging potential therapeutic implications for immunotherapy in animal models and human diseases.

The Oncogenic Signaling Disruptor, NDRG1: Molecular and Cellular Mechanisms of Activity

“…The CBL family, in mammals, consists of c-Cbl, Cbl-b and Cbl-3 proteins [ 109 ]. c-Cbl is encoded by the Cbl gene located on chromosome 11, position 11q23.3, which—when translated—results in a 906 amino acid protein with an estimated molecular weight of 120 kDa [ 110 , 111 , 112 ]. c-Cbl is primarily a cytoplasmic protein expressed in virtually all cell types.…”

“…However, it associates with the membrane upon receptor tyrosine kinase (RTK) stimulation/phosphorylation, and has even been shown to localize to immunological synapses in T-cells [ 109 ]. Cbl proteins are important E3 ubiquitin ligases that initiate the degradation of proteins by recruiting E2 (ubiquitin-conjugating enzyme), which catalyzes the transfer of ubiquitin (Ub) from E2 to the protein target [ 109 , 111 , 113 ]. Ubiquitinated proteins are then targeted to the lysosome or proteasome for degradation depending on the pattern of Ub addition [ 109 ].…”

“…The CBL family regulates immune system components, protein tyrosine kinase signaling, and an array of downstream signaling proteins, primarily by ubiquitination [ 109 , 111 , 113 ]. All Cbl proteins have an N -terminal tyrosine kinase binding (TKB) domain that recognizes specific phospho-tyrosine residues on target proteins, such as RTKs ( Figure 12 ).…”

“…A C -terminal proline-rich region follows the RF domain and allows interaction with proteins containing the Src homology 3 (SH3) domain (e.g., Grb2). This latter region is followed by a tyrosine-rich sequence, which becomes a binding motif for SH2 (Src homology 2) domain-containing proteins, such as Crk and p85, after phosphorylation [ 109 , 111 , 112 , 113 ]. CBL proteins terminate with a ubiquitin-associated domain (UAD) that is crucial for CBL proteins to form dimers [ 109 , 111 , 112 , 113 ] ( Figure 12 ).…”

“…c-CBL is involved in the negative regulation of RTKs such as PDGF, EGFR, or c-Met, acting as a negative feedback mechanism [ 109 , 111 , 113 , 114 ]. Growth factor binding induce3s RTK auto-phosphorylation and recruits c-CBL to the activated receptor via the Grb2 adaptor protein.…”