Biomedical subjects

Marion M Nau

Publications and source records attributed to Marion M Nau.

4 recordsLinked to original sources

PubMed2006

Regulating the regulator: negative regulation of Cbl ubiquitin ligases.

Cbl proteins are regulators of signal transduction through many pathways and, consequently, regulate cell function and development. They are ubiquitin ligases that ubiquitinate and target many signaling molecules for degradation. The Cbl proteins themselves are regulated by an increasingly complex network of interactions that fine-tune the effects that Cbl proteins have on signaling. The negative regulation of Cbl protein function can occur via cis-acting structural elements that prevent inappropriate ubiquitin ligase activity, degradation of the Cbl proteins, inhibition without degradation owing to interaction with other signaling proteins, deubiquitination of Cbl substrates, and regulation of assembly of the endosomal ESCRT-I complex. Defects in the regulatory mechanisms that control Cbl function are implicated in the development of immunological and malignant diseases.

Animals↗

PubMed2004

Cbl-b interacts with ubiquitinated proteins; differential functions of the UBA domains of c-Cbl and Cbl-b.

Cbl proteins are ubiquitin protein ligases, which ubiquitinate activated tyrosine kinases and target them for degradation. Both c-Cbl and Cbl-b have an ubiquitin associated (UBA) domain at their C-terminal end. We observed that high molecular weight ubiquitinated proteins constitutively coimmunoprecipitated with transfected and endogenous Cbl-b, but not c-Cbl. The binding site for these ubiquitinated proteins was mapped to the UBA domain of Cbl-b (UBAb). GST-fusion proteins containing the UBAb interacted with ubiquitinated proteins and polyubiquitin chains in vitro, whereas those containing the UBA domain of c-Cbl (UBAc) did not. The UBAb had a much greater affinity for polyubiquitin chains than for monoubiquitin. Analysis of the UBAb and UBAc demonstrate that the affinity for ubiquitin is determined by multiple amino-acid differences between the two domains. Overexpression of the UBAb, but not overexpression of the UBAc, inhibited a variety of ubiquitin-mediated processes such as degradation of ubiquitinated proteins (i.e. EGFR, Mdm-2, and Siah-1). This in vivo result is consistent with the differences in ubiquitin binding observed in vitro between the UBAb and UBAc. This difference in ubiquitin-binding may reflect distinct regulatory functions of c-Cbl and Cbl-b.

Adaptor Proteins, Signal Transducing↗

PubMed2003

Comparative genomic organization of the cbl genes.

The genomic organization of cbl genes from a variety of mammalian and non-mammalian species was determined by a combination of cloning and database searches. Humans and mice have three cbl genes (c-cbl,(1) cblb, and cblc) which show remarkable conservation of the intron/exon structure over the region of the genes which encode the highly conserved N-terminal region of the proteins including the RING finger. Searches of genomic, cDNA, and EST databases revealed that one or more cbl genes exist in chordates, insects, and worms. Comparison of the complexity and genomic organization of the cbl gene family and the predicted Cbl proteins from various species suggests that the three mammalian cbl genes arose by two duplications of an ancestral gene. The genomic organization of the cbl genes from various species provides insight into the evolution of the cbl gene family.

Amino Acid Sequence↗

PubMed2003

Cbl-3-deficient mice exhibit normal epithelial development.

Cbl family proteins are evolutionarily conserved ubiquitin ligases that negatively regulate signaling from tyrosine kinase-coupled receptors. The mammalian cbl family consists of c-Cbl, Cbl-b, and the recently cloned Cbl-3 (also known as Cbl-c). In this study, we describe the detailed expression pattern of murine Cbl-3 and report the generation and characterization of Cbl-3-deficient mice. Cbl-3 exhibits an expression pattern distinct from those of c-Cbl and Cbl-b, with high levels of Cbl-3 expression in epithelial cells of the gastrointestinal tract and epidermis, as well as the respiratory, urinary, and reproductive systems. Cbl-3 expression was not detected in nonepithelial cells, but within epithelial tissues, the levels of Cbl-3 expression varied from undetectable in the alveoli of the lungs to very strong in the cecum and colon. Despite this restricted expression pattern, Cbl-3-deficient mice were viable, healthy, and fertile and displayed no histological abnormalities up to 18 months of age. Proliferation of epithelial cells in the epidermises and gastrointestinal tracts was unaffected by the loss of Cbl-3. Moreover, Cbl-3 was not required for attenuation of epidermal growth factor-stimulated Erk activation in primary keratinocytes. Thus, Cbl-3 is dispensable for normal epithelial development and function.

Animals↗