Through the process of alternative
Through the process of alternative splicing, the IKZF1 gene is capable of encoding a large number of Ikaros isoforms (Molnar et al., 1996). Some of these isoforms were shown to have distinct functions (Li et al., 2011, Ronni et al., 2007). Ikaros protein contains four zinc fingers at the N-terminus that directly interacts with DNA and determine DNA-binding affinity and specificity of Ikaros, and two zinc fingers at the C-terminus that participate in protein-protein interactions (Molnár and Georgopoulos, 1994). The protein-protein interactions include the formation of dimers with other Ikaros isoforms or the other members of Ikaros family proteins (Li et al., 2011, Molnár and Georgopoulos, 1994). Isoforms of Ikaros that lack DNA-binding zinc fingers can form a functionally inactive complex that can impair function of the full-length Ikaros (Sun et al., 1996).
Ikaros utilizes Magnolol remodeling to activate or repress the transcription of its target genes (Su et al., 2004). Ikaros directly associates with histone deacetylases HDAC1 and HDAC2 and can recruit them to the upstream regulatory elements of its target genes (Kim et al., 1999, Koipally et al., 1999a, Koipally et al., 1999b). The ability of Ikaros to regulate transcription of its target genes is often dependent on its ability to localize to pericetromeric heterochromatin (Brown et al., 1997, Cobb et al., 2000, Liberg et al., 2003). Ikaros binds to the upstream regulatory element (URE) of its target genes and assists in their recruitment to pericentromeric heterochromatin (Brown et al., 1997).
Conclusion The first mechanism involves direct phosphorylation of target proteins (phosphorylation of PTEN by CK2 and GSK-3). The second mechanism involves transcriptional regulation of PI3K-promoting genes (via CK2-mediated phosphorylation of Ikaros) (Fig. 1). The role of Ikaros in regulating the PI3K pathway illustrates a major distinction from the typical cross-talk between two signaling pathways that involves only posttranslational modifications of the same target proteins.
Conflict of interest
Acknowledgements This work has been supported by Hyundai Hope on Wheels Scholar Grant Award, Alex's Lemonade Stand Grant, Bear Necessities Pediatric Cancer Foundation, the Four Diamonds Fund of the Pennsylvania State University, College of Medicine, and the John Wawrynovic Leukemia Research Scholar Endowment (SD); by NIHR01 CA209829 (SD and KJP), by St. Baldrick's Foundation Fellows Award and Hyundai Hope on Wheels Fellowship Grant Award (CG).
Introduction CK2 is a constitutive and ubiquitous Ser/Thr protein kinase that functions as a global regulator of cell survival often found deregulated in cancer and other complex diseases , , , . The CK2 consensus sequence, [pS/pT]- P -x-[E/D] or [pS/pT]- P -x-pS, constitutes a small motif found so far in more than 300 experimentally determined CK2 substrates among different organisms and viral proteins . Such promiscuity connects CK2-dependent phosphorylation with key cellular biological processes and pathways involved in DNA repair , apoptosis , survival/proliferation , and viral infection . The mammalian CK2 holoenzyme is a heterotetramer composed of two catalytic (CK2α and/or CK2α′) and two regulatory subunits (CK2β) with a α2-β2 stoichiometry (α2-β2, α′2-β2 or α1α′1-β2) , . The heterotetramer can dissociate under certain conditions with evidences indicating the presence of individual subunits . The free catalytic monomers maintain its activity against a range of substrates while the regulatory subunits might display CK2-independent functions targeting DNA repair, cell cycle and protein kinases as A-Raf, c-Mos and Chk1 . In the holoenzyme, CK2β is a substrate-dependent modulator of kinase activity. In accordance, Pinna grouped the CK2 substrates in three classes based on the subunit composition of active enzyme . Class-I includes CK2 substrates modified either by CK2α or the holoenzyme, poorly influenced by the CK2β subunit . Class-II, substrates such as calmodulin (CALM), phosphorylated by CK2α alone with holoenzyme formation inhibiting kinase activity ; this regulatory effect is mitigated with the addition of polycationic molecules (e.g., histones, polylysine and polyamines) . Class-III substrates are beta-dependent and their phosphorylation relies on the integrity of the N terminal acidic loop of this subunit (sequence D55LEPDEELED64). This is true for Rev ,  and eIF2β  where electrostatic contacts between basic residues on the substrates and the acidic loop enhance kinase-substrate binding.