Phosphorylation Controls Ikaros's Ability To Negatively Regulate the G₁-S Transition

Abstract

Ikaros is a key regulator of lymphocyte proliferative responses. Inactivating mutations in Ikaros cause antigen-mediated lymphocyte hyperproliferation and the rapid development of leukemia and lymphoma. Here we show that Ikaros's ability to negatively regulate the G₁-S transition can be modulated by phosphorylation of a serine/threonine-rich conserved region (p1) in exon 8. Ikaros phosphorylation in p1 is induced during the G₁-S transition. Mutations that prevent phosphorylation in p1 increase Ikaros's ability to impede cell cycle progression and its affinity for DNA. Casein kinase II, whose increased activity in lymphocytes leads to transformation, is a key player in Ikaros p1 phosphorylation. We thus propose that Ikaros's activity as a regulator of the G₁-S transition is controlled by phosphorylation in response to signaling events that downmodulate its DNA binding activity.

We thank T. Kitamura for the pMX-GFP-IRES vector. We are grateful to A. Liu for technical assistance with gel shifts; Joanne Yetz-Aldape for cell sorting; Taj Pathan for mouse care; and J. Aramburu, B. Morgan, J. M. Redondo, J. Koipally, and the members of the Georgopoulos laboratory for careful reading and valuable comments on the manuscript.

P.G.-D.A. is a Fellow of the Leukemia and Lymphoma Society and was also supported by Ministry of Education and Culture of Spain. K.M. was supported by the Yamanouchi Foundation for Research on Metabolic Disorders and by the Mochida Memorial Foundation for Medical and Pharmaceutical Research. This research was supported by NIH grant RO1-AI380342 to K.G.