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    • br GSK Glycogen synthase kinase GSK

    2022-08-09


    GSK-3 Glycogen synthase kinase-3 (GSK-3) is a ubiquitous serine/threonine kinase that is involved in multiple signaling pathways that are crucial for cellular metabolism and proliferation (Doble and Woodgett, 2003, Frame and Cohen, 2001, Grimes and Jope, 2001, Woodgett, 1990). GSK-3 is known to directly phosphorylate at least 40 substrates, although the actual number of substrates is probably much larger (Linding et al., 2007, Sutherland, 2011). Advances in understanding the role of GSK-3 in cellular regulation revealed that this kinase has an important role in the regulation of Wnt, Notch, hedghog, nuclear factor of activated T cells (NF-AT), cyclic adenosine monophosphate (cAMP) and phosphatidylinositol 3-kinase (PI3K) (Frame and Cohen, 2001, Grimes and Jope, 2001). GSK-3 protein can exist in two forms (GSK-3α and GSK-3β) that are encoded by two separate genes (Woodgett, 1990). These GSK-3 proteins can be regulated by distinct post-translational mechanisms involving Angiotensin 1/2 (1-9) mg that are unique for each protein. Phosphorylation of GSK-3β at serine 389 (S389) by p38 mitogen-activated protein kinase (MAPK) in response to DNA double-strand breaks, inhibits activity of this protein in thymus (Thornton et al., 2008, Thornton et al., 2016). Since S389 is absent in GSK-3α, these data reveal distinct functions and regulatory networks for the two GSK3 proteins. Further, GSK-3α, but not GSK-3β has been shown to function as a suppressor of aging and plays a role in atherosclerosis (Banko et al., 2014, Zhou et al., 2013).
    The IKZF1 gene encodes Ikaros, a kruppel-like zinc finger DNA-binding protein that functions as a master regulator of hematopoiesis (Georgopoulos et al., 1992, Georgopoulos et al., 1994, Lo et al., 1991). The absence of Ikaros has a detrimental effect on normal hematopoiesis as evidenced by the loss of B, NK, and dendritic cells as well as reduced T cells (Cortes et al., 1999, Georgopoulos et al., 1994). The critical role of Ikaros in the immune system (Avitahl et al., 1999, Ernst et al., 1993), as well as in myeloid differentiation (Dumortier et al., 2003) has been proven. The role of Ikaros, as a tumor suppressor was first identified in 1994 in Ikaros haplo-knockout mice (Georgopoulos et al., 1994, Winandy et al., 1995). Mice that are missing one copy of Ikaros develop T-cell leukemia with 100% penetrance (Winandy et al., 1995). Reintroduction of Ikaros into these leukemia cells results in cessation of cell growth and partial induction of T-cell differentiation (Kathrein et al., 2005). The deletion of Ikaros in humans has been directly associated with the development of high-risk leukemia (Mullighan et al., 2007) and primary immunodeficiency diseases. IKZF1 deletion has been linked with an increase in relapse rate of up to 12-fold in acute lymphoblastic leukemia (Kuiper et al., 2010). Among B-ALL, a deletion of one IKZF1 alelle is found in approximately 80% of BCR-ABL1+ ALL (Mullighan et al., 2008) and Ph-like ALL (Den Boer et al., 2009) as well as ∼20% of patients that are BCR-ABL negative (Mullighan et al., 2007). Approximately 9% of T-cell ALL (Zhang et al., 2012) and 11% of early precursor T cell ALL (ETP-ALL) show mutation or inactivation of one IKZF1 allele (Zhang et al., 2012). Germline mutation of IKZF1 has also been associated with congenital pancytopenia (Goldman et al., 2012). 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).