Strict regulation of signaling by receptor tyrosine kinases (RTKs) is essential for normal biological processes, and disruption of this regulation can lead to tumor initiation and progression. Signal duration by the Met RTK is mediated in part by the E3 ligase Cbl. Cbl is recruited to Met upon kinase activation and promotes ubiquitination, trafficking, and degradation of the receptor. The Met R...

The CBL ubiquitin ligase targets a variety of activated tyrosine kinases (TKs) for degradation. Many TKs are mutationally or autocrine activated and/or often overexpressed at the mRNA and protein levels in acute leukemias. We hypothesized that CBL is mutated in patients with acute myeloid leukemia (AML). Four of 12 patients and the MOLM-13 cell line harbored c-CBL mutations, either RNA splicing...

OBJECTIVE Functional cobalamin (Cbl) deficiency (i.e., high methylmalonic acid [MMA] values despite normal serum Cbl levels) is common in the elderly and associated with neuropathy and anemia. Because diabetes is also common in the elderly and diabetic neuropathy resembles that of Cbl deficiency, the role of diabetes in functional Cbl deficiency was explored. RESEARCH DESIGN AND METHODS A ret...

BACKGROUND A substantial proportion of patients referred for plasma vitamin B12 (cobalamin [Cbl]) measurement present with high Cbl levels, which have been reported in patients with different cancer types. However, the cancer risk among patients with newly diagnosed high Cbl levels has not been adequately examined. METHODS We conducted this cohort study using population-based Danish medical r...

c-Cbl protein functions as an E3 ligase and scaffolding protein, where 3 residues, Y700, Y731, and Y774, upon phosphorylation, have been shown to initiate several signaling cascades. In this study, we investigated the role of these phospho-tyrosine residues in the platelet functional responses after integrin engagement. We observed that c-Cbl Y700, Y731 and Y774 undergo phosphorylation upon pla...

The uptake of 57Co-cyanocobalamin (CN-Cbl) and its conversion to 5-deoxyadenosylcobalamin (Ado-Cbl), methylcobalamin (Me-Cbl), and hydroxocobalamin (OH-Cbl) has been studied in phytohemagglutinin (PHA)-transformed lymphocytes from normal subjects and patients with patients with pernicious anemia. Uptake and conversion were much greater by PHA-stimulated lymphocytes than by mature non-transforme...

Methionine synthase catalyzes the conversion of N5-methyltetrahydrofolate and homocysteine to tetrahydrofolate and methionine. Methylcobalamin (Me-Cbl) is tightly bound to methionine synthase and is required for enzymatic activity. When added to crude tissue homogenates, Me-Cbl stimulates methionine synthase but similar stimulation is observed with hydroxocobalamin, cyanocobalamin (CN-Cbl), and...

Three distinct classes of human mutations (cbl A, cbl B, and cbl C) cause defective synthesis of cobalamin (Cbl; vitamin B(12)) coenzymes. Cultured fibroblasts from that unique class (cbl C) deficient in the synthesis of both Cbl coenzymes, 5'-deoxyadenosylcobalamin (AdoCbl) and methylcobalamin (MeCbl), were used to explore the underlying defect. We compared the uptake of transcobalamin II(TC I...

BACKGROUND Diagnosing cobalamin (Cbl) deficiency as a cause of polyneuropathy (PN) is problematic, as the frequency of both disorders increases with age, and serum Cbl levels can be difficult to interpret. OBJECTIVES To identify unique clinical or laboratory features among PN patients with Cbl deficiency and to examine the role of testing of serum metabolite levels in the identification of Cb...