title: The TBC1D15 oncoprotein controls stem cell self-renewal through destabilization of the Numb-p53 complex.
abstract: Stem cell populations are maintained through self-renewing divisions in which one daughter cell commits to a specific fate while the other retains the multipotent characteristics of its parent. The p53 tumor suppressor, in conjunction with its interacting partner protein Numb, preserves this asymmetry and functions as a vital barrier against the unchecked expansion of tumor stem cell pools; however, little is known about the biological control of the Numb-p53 interaction. We show here that Numb and p53 are the constituents of a high molecular mass complex, which is disintegrated upon activation of aPKCζ, a Numb kinase. Using large-scale affinity purification and tandem mass spectrometry, we identify TBC1D15 as a Numb-associated protein and demonstrate that its amino-terminal domain disengages p53 from Numb, triggering p53 proteolysis and promoting self-renewal and pluripotency. Cellular levels of TBC1D15 are diminished upon acute nutrient deprivation through autophagy-mediated degradation, indicating that TBC1D15 serves as a conduit through which cellular metabolic status is linked to self-renewal. The profound deregulation of TBC1D15 expression exhibited in a diverse array of patient tumors underscores its proposed function as an oncoprotein.
authors.affiliation: Department of Molecular Microbiology and Immunology, University of Southern California, Keck School of Medicine, Los Angeles, CA, USA. defeldma@usc.edu
authors.forename: Douglas E
authors.initials: DE
authors.lastname: Feldman
authors.forename: Chialin
authors.initials: C
authors.lastname: Chen
authors.forename: Vasu
authors.initials: V
authors.lastname: Punj
authors.forename: Keigo
authors.initials: K
authors.lastname: Machida
mesh_terms: D000595:Amino Acid Sequence; D020690:GTPase-Activating Proteins / Q000502:physiology*; D006801:Humans; D008565:Membrane Proteins / Q000737:chemistry / Q000378:metabolism*; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000378:metabolism*; D013234:Stem Cells / Q000166:cytology*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D020690:GTPase-Activating Proteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; C113026:NUMB protein, human; C550073:TBC1D15 protein, human; D016159:Tumor Suppressor Protein p53