title: Protein tyrosine kinase regulation by ubiquitination: critical roles of Cbl-family ubiquitin ligases.
abstract: Protein tyrosine kinases (PTKs) coordinate a broad spectrum of cellular responses to extracellular stimuli and cell-cell interactions during development, tissue homeostasis, and responses to environmental challenges. Thus, an understanding of the regulatory mechanisms that ensure physiological PTK function and potential aberrations of these regulatory processes during diseases such as cancer are of broad interest in biology and medicine. Aside from the expected role of phospho-tyrosine phosphatases, recent studies have revealed a critical role of covalent modification of activated PTKs with ubiquitin as a critical mechanism of their negative regulation. Members of the Cbl protein family (Cbl, Cbl-b and Cbl-c in mammals) have emerged as dominant "activated PTK-selective" ubiquitin ligases. Structural, biochemical and cell biological studies have established that Cbl protein-dependent ubiquitination targets activated PTKs for degradation either by facilitating their endocytic sorting into lysosomes or by promoting their proteasomal degradation. This mechanism also targets PTK signaling intermediates that become associated with Cbl proteins in a PTK activation-dependent manner. Cellular and animal studies have established that the relatively broadly expressed mammalian Cbl family members Cbl and Cbl-b play key physiological roles, including their critical functions to prevent the transition of normal immune responses into autoimmune disease and as tumor suppressors; the latter function has received validation from human studies linking mutations in Cbl to human leukemia. These newer insights together with embryonic lethality seen in mice with a combined deletion of Cbl and Cbl-b genes suggest an unappreciated role of the Cbl family proteins, and by implication the ubiquitin-dependent control of activated PTKs, in stem/progenitor cell maintenance. Future studies of existing and emerging animal models and their various cell lineages should help test the broader implications of the evolutionarily-conserved Cbl family protein-mediated, ubiquitin-dependent, negative regulation of activated PTKs in physiology and disease.
authors.affiliation: Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: Bhopal
authors.initials: B
authors.lastname: Mohapatra
authors.forename: Gulzar
authors.initials: G
authors.lastname: Ahmad
authors.forename: Scott
authors.initials: S
authors.lastname: Nadeau
authors.forename: Neha
authors.initials: N
authors.lastname: Zutshi
authors.forename: Wei
authors.initials: W
authors.lastname: An
authors.forename: Sarah
authors.initials: S
authors.lastname: Scheffe
authors.forename: Lin
authors.initials: L
authors.lastname: Dong
authors.forename: Dan
authors.initials: D
authors.lastname: Feng
authors.forename: Benjamin
authors.initials: B
authors.lastname: Goetz
authors.forename: Priyanka
authors.initials: P
authors.lastname: Arya
authors.forename: Tameka A
authors.initials: TA
authors.lastname: Bailey
authors.forename: Nicholas
authors.initials: N
authors.lastname: Palermo
authors.forename: Gloria E O
authors.initials: GE
authors.lastname: Borgstahl
authors.forename: Amarnath
authors.initials: A
authors.lastname: Natarajan
authors.forename: Srikumar M
authors.initials: SM
authors.lastname: Raja
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
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D006801:Humans; D051379:Mice; D008954:Models, Biological; D011505:Protein-Tyrosine Kinases / Q000378:metabolism* / Q000502:physiology; D050721:Proto-Oncogene Proteins c-cbl / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D025801:Ubiquitin / Q000378:metabolism; D054875:Ubiquitination / Q000502:physiology*
chemical_list: D025801:Ubiquitin; D050721:Proto-Oncogene Proteins c-cbl; D011505:Protein-Tyrosine Kinases