Cbl and human myeloid neoplasms: the Cbl oncogene comes of age

Abstract

Cbl was originally discovered in 1989 as the cellular homolog of the v-Cbl oncogene, the transforming gene of the Cas NS-1 murine retrovirus that causes myeloid leukemia and lymphomas in mice. Cbl is a member of a family of RING finger ubiquitin ligases that negatively regulate signaling by tyrosine kinases and that function as adaptor proteins to regulate signaling positively. Until the past 2 years, there was little evidence that Cbl proteins were involved in human malignancies. Recent publications have shown homozygous mutations in Cbl in human myeloid neoplasms. Although in vitro and animal transformation models suggested that mutant forms of Cbl acted as an oncogene, the cellular role suggested that the protein could serve as a tumor suppressor gene. The recent data begin to reconcile this paradox as the loss of ubiquitin ligase function (the tumor suppressor function) is coupled to the maintenance of the positive signaling function (the oncogene function). These data also provide insight into potential therapeutic approaches to myeloid disorders harboring Cbl mutations.

Figure 1

A, The domain organization of the mammalian Cbl proteins. v-Cbl: the Gag-Cbl fusion protein of the Cas NS-1 murine retrovirus; Cbl: the human proto-oncogene of v-Cbl; Cbl-b: the second human Cbl protein; Cbl-c: the third human Cbl protein The tyrosine kinase binding domain (TKB) is comprised of a 4-helix bundle (4H), an EF hand (EF), and a variant SH2 domain (SH2). The linker (L), RING finger (RF), proline-rich (P), and the ubiquitin-associated (UBA) domains are indicated on the diagram. The tyrosines in the C-terminus of Cbl and Cbl-b that are phosphorylated are indicated. B, Compilation of Cbl mutations in the linker and RF domains from human myeloid neoplasms. Sequence shown includes the linker region and RF. The critical linker tyrosine (Y371) is shown in blue. The zinc coordinating amino acids are shown in red. Missense mutations in the linker and RF of Cbl are indicated above the sequence by black arrows, frame shift mutations are indicated by red arrows, and an insertion is indicated by an open arrow. Deletion mutations are indicated by the brackets below the sequence. Exon 8 deletions were found in 5 samples indicated in the parentheses. C, Cbl pathways. Cbl functions as a tumor suppressor by E3 dependent ubiquitination and downregulation of activated RTKs as indicated to the right of the figure. Cbl can function also as an oncogene by mediating adaptor function dependant activation of downstream signaling to the PI3K/AKT pathway.