title: Oncogenic Signaling by Leukemia-Associated Mutant Cbl Proteins.
abstract: Members of the Cbl protein family (Cbl, Cbl-b, and Cbl-c) are E3 ubiquitin ligases that have emerged as critical negative regulators of protein tyrosine kinase (PTK) signaling. This function reflects their ability to directly interact with activated PTKs and to target them as well as their associated signaling components for ubiquitination. Given the critical roles of PTK signaling in driving oncogenesis, recent studies in animal models and genetic analyses in human cancer have firmly established that Cbl proteins function as tumor suppressors. Missense mutations or small in-frame deletions within the regions of Cbl protein that are essential for its E3 activity have been identified in nearly 5% of leukemia patients with myelodysplastic/myeloproliferative disorders. Based on evidence from cell culture studies, in vivo models and clinical data, we discuss the potential signaling mechanisms of mutant Cbl-driven oncogenesis. Mechanistic insights into oncogenic Cbl mutants and associated animal models are likely to enhance our understanding of normal hematopoietic stem cell homeostasis and provide avenues for targeted therapy of mutant Cbl-driven cancers.
authors.affiliation: Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, 985950 Nebraska Medical Center Omaha, NE 68198-5950, USA ; Departments of Genetics, Cell Biology & Anatomy, University of Nebraska Medical Center, 985950 Nebraska Medical Center Omaha, NE 68198-5950, USA.
authors.forename: Scott
authors.initials: S
authors.lastname: Nadeau
authors.forename: Wei
authors.initials: W
authors.lastname: An
authors.forename: Nick
authors.initials: N
authors.lastname: Palermo
authors.forename: Dan
authors.initials: D
authors.lastname: Feng
authors.forename: Gulzar
authors.initials: G
authors.lastname: Ahmad
authors.forename: Lin
authors.initials: L
authors.lastname: Dong
authors.forename: Gloria E O
authors.initials: GE
authors.lastname: Borgstahl
authors.forename: Amarnath
authors.initials: A
authors.lastname: Natarajan
authors.forename: Mayumi
authors.initials: M
authors.lastname: Naramura
authors.forename: Vimla
authors.initials: V
authors.lastname: Band
authors.forename: Hamid
authors.initials: H
authors.lastname: Band
keywords: Cbl; Cellular signaling; E3 ubiquitin ligase; Hematopoietic; Leukemia; MDS/MPN; Tyrosine kinase