Molecular pathways: cbl proteins in tumorigenesis and antitumor immunity-opportunities for cancer treatment

Abstract

The Cbl proteins are a family of ubiquitin ligases (E3s) that regulate signaling through many tyrosine kinase-dependent pathways. A predominant function is to negatively regulate receptor tyrosine kinase (RTK) signaling by ubiquitination of active RTKs, targeting them for trafficking to the lysosome for degradation. Also, Cbl-mediated ubiquitination can regulate signaling protein function by altered cellular localization of proteins without degradation. In addition to their role as E3s, Cbl proteins play a positive role in signaling by acting as adaptor proteins that can recruit signaling molecules to the active RTKs. Cbl-b, a second family member, negatively regulates the costimulatory pathway of CD8 T cells and also negatively regulates natural killer cell function. The different functions of Cbl proteins and their roles both in the development of cancer and the regulation of immune responses provide multiple therapeutic opportunities. Mutations in Cbl that inactivate the negative E3 function while maintaining the positive adaptor function have been described in approximately 5% of myeloid neoplasms. An improved understanding of how the signaling pathways [e.g., Fms-like tyrosine kinase 3 (Flt3), PI3K, and signal transducer and activator of transcription (Stat)] are dysregulated by these mutations in Cbl has helped to identify potential targets for therapy of myeloid neoplasms. Conversely, the loss of Cbl-b leads to increased adaptive and innate antitumor immunity, suggesting that inhibiting Cbl-b may be a means to increase antitumor immunity across a wide variety of tumors. Thus, targeting the pathways regulated by Cbl proteins may provide attractive opportunities for treating cancer.

Figure 1

Cbl pathways. A. All Cbl proteins are recruited to activated RTKs where they mediate ubiquitination and downregulation of the RTKs. The ubiquitinated RTKs are degraded by the lysosome. Thus loss of the E3 function of Cbl results in sustained signaling by RTKs. B. Cbl proteins can serve as adaptor proteins which recruit signaling molecules such as PI3 Kinase to the activated RTK. The mutant proteins that have lost E3 function frequently retain the ability to activate PI3K by this mechanism and so function as oncogenes. C. Cbl-b is a negative regulator of the CD28 costimulatory pathway in T-Cells. CD28 is activated by B7 molecules on the surface of antigen presenting cells (APC). Cbl-b ubiquitinates the p85 subunit of PI3K, preventing its recruitment to the activated CD28. The loss of Cbl-b results in hyperactive immunity, including anti-tumor immunity. D. Cbl-b is a negative regulator of NK cell anti-tumor acitivity. Growth arrest specific-6 (Gas6) is an activating ligand for the TAM receptors. Cbl-b is activated downstream of the TAM RTKs and inhibits NK cell activation – presumably by ubiquitinating an unknown substrate (X) that is required for activation. Cbl-b also can ubiquitinate the TAM receptors. The loss of Cbl-b results in increased NK cell anti-tumor activity.