Control of activating transcription factor 4 (ATF4) persistence by multisite phosphorylation impacts cell cycle progression and neurogenesis.
Organogenesis is a highly integrated process with a fundamental requirement for precise cell cycle control. Mechanistically, the cell cycle is composed of transitions and thresholds that are controlled by coordinated post-translational modifications. In this study, we describe a novel mechanism controlling the persistence of the transcription factor ATF4 by multisite phosphorylation. Proline-directed phosphorylation acted additively to regulate multiple aspects of ATF4 degradation. Stabilized ATF4 mutants exhibit decreased β-TrCP degron phosphorylation, β-TrCP interaction, and ubiquitination, as well as elicit early G(1) arrest. Expression of stabilized ATF4 also had significant consequences in the developing neocortex. Mutant ATF4 expressing cells exhibited positioning and differentiation defects that were attributed to early G(1) arrest, suggesting that neurogenesis is sensitive to ATF4 dosage. We propose that precise regulation of the ATF4 dosage impacts cell cycle control and impinges on neurogenesis.
Frank
Christopher L
CL
From the Massachusetts Institute of Technology, Picower Institute for Learning and Memory, the Howard Hughes Medical Institute, Cambridge, Massachusetts 02139, the Stanley Center for Psychiatric Research.
Ge
Xuecai
X
From the Massachusetts Institute of Technology, Picower Institute for Learning and Memory, the Howard Hughes Medical Institute, Cambridge, Massachusetts 02139, the Stanley Center for Psychiatric Research.
Xie
Zhigang
Z
From the Massachusetts Institute of Technology, Picower Institute for Learning and Memory, the Howard Hughes Medical Institute, Cambridge, Massachusetts 02139, the Stanley Center for Psychiatric Research; Departments of Neurosurgery and Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, Massachusetts 02118.
Zhou
Ying
Y
From the Massachusetts Institute of Technology, Picower Institute for Learning and Memory, the Howard Hughes Medical Institute, Cambridge, Massachusetts 02139, the Stanley Center for Psychiatric Research.
Tsai
Li-Huei
LH
From the Massachusetts Institute of Technology, Picower Institute for Learning and Memory, the Howard Hughes Medical Institute, Cambridge, Massachusetts 02139, the Stanley Center for Psychiatric Research; Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts 02139. Electronic address: lhtsai@mit.edu.
D051701:Activating Transcription Factor 4 / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D005260:Female; D016193:G1 Phase / Q000502:physiology*; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D009154:Mutation; D041681:NIH 3T3 Cells; D019579:Neocortex / Q000166:cytology / Q000196:embryology*; D055495:Neurogenesis / Q000502:physiology*; D010766:Phosphorylation / Q000502:physiology; D054875:Ubiquitination / Q000502:physiology*
C497109:ATF4 protein, human; C081452:Atf4 protein, mouse; D051701:Activating Transcription Factor 4