Is CK2 a therapeutic target for human diseases?
May 17, 2021 · CK2 general features. CK2 (previously called casein kinase 2 or CK-II) is one of the first identified protein kinases. 1 It phosphorylates hundreds of physiological substrates, 2 and is one of the major contributors to the generation of the human phospho-proteome. 3 Structurally, mammalian CK2 is a tetrameric enzyme, composed of two catalytic and two regulatory subunits.
Is CK2 a therapeutic target in medulloblastoma?
Mar 05, 2017 · Protein kinase CK2 is a small family of protein kinases that has been implicated in an expanding array of biological processes. While it is widely accepted that CK2 is a regulatory participant in a multitude of fundamental cellular processes, CK2 is often considered to be a constitutively active enzyme which raises questions about how it can be a regulatory …
What is the pathophysiology of CK2?
CK2 status in normal vs. cancer cells. Early studies of protein kinase signaling in the prostate [] led to identification of CK2 as an important signal in the androgen- and growth factor-mediated regulation of growth in a normal cell growth model [].A key feature of CK2 regulation of cell growth and death relates to nuclear signaling, as evidenced by its shuttling to and from nuclear ...
Is CK2 a therapeutic target after optic nerve injury?
Glioblastoma is the most prevalent and malignant primary brain tumor in adults, and its response to current therapies is limited. Protein kinase CK2 is overexpressed in glioblastoma and regulates glioblastoma cell survival, proliferation, and migration and brain tumorigenesis.
What is CK2 in biology?
CK2 (casein kinase II) is a ubiquitously expressed and evolutionarily conserved pleiotropic protein kinase that is essential for viability. CK2 is constitutively active, and its activity is independent of either known second messengers or phosphorylation events (39). The levels of CK2 are elevated in a wide variety of tumors, and CK2 can be oncogenic when overexpressed in animals (46), suggesting its important role in cell growth and neoplasia (56). In addition, CK2 has been implicated to be essential for many biological processes such as cell cycle progression (40), proliferation (16), cell survival (2, 26), oncogenic processes (46, 56), and circadian rhythms (3, 25). Various kinds of CK2 substrates both in vitro and in vivo have been reported (29). Surprisingly, even long years after its discovery in the 1950s, molecular mechanisms by which CK2 regulates a vast array of cellular functions remain unknown.
What is the unique phosphorylation site of Cdc37?
Ser13 is the unique phosphorylation site of Cdc37 in mammalian cells.
What is Ser13 of Cdc37?
Ser13 of Cdc37 is essential for the association of Cdc37 with MOK.
What is the protein kinase domain of MOK?
Protein kinase domain of MOK was essential for the binding of Cdc37. Various MOK deletion mutants with a FLAG tag were expressed in COS7 cells and immunoprecipitated. (A) Amounts of MOK and its mutants in the immunoprecipitates were examined by Western blotting. Bands corresponding to deletion mutant proteins are indicated by asterisks [except MOK(N107) (see the text)]. Lane 1, control (not transfected); lane 2, MOK(WT); lane 3, MOK(N107); lane 4, MOK(N178); lane 5, MOK(N285); lane 6, MOK(D8-078); lane 7, MOK(D8-195); lane 8, MOK(D8-309). (B) Associations of endogenous Cdc37 with the same set of MOK deletion mutants as in panel A were examined by coimmunoprecipitation experiments and revealed by Western blotting with anti-Cdc37 antibody. Lane marks are the same as those for panel A. The positions of Cdc37, immunoglobulin heavy-chain (HC), immunoglobulin light-chain (LC), and molecular weight markers are indicated. (C) The relationship between structures and the Cdc37 binding abilities of MOK deletion mutants is schematically illustrated. ++, binds strongly; +, binds well; −, no binding.
What is the N-terminal region of Cdc37?
The N-terminal region (amino acids 1 to 93) of rat Cdc37 contains 3 serines and 2 threonines. All of them are clustered in the most N-terminal region of Cdc37 (amino acids 1 to 30), and this region shows the highest conservation between species (Fig. (Fig.2A).2A). One of these serines, Ser13 of rat Cdc37 (Fig. (Fig.2A),2A), is followed by a conserved stretch of acidic amino acids, making Ser13 a consensus sequence motif for CK2 phosphorylation. To show that Ser13 of Cdc37 is the CK2 phosphorylation site, we made two point mutants in which Ser13 was changed into Ala [Cdc37(13SA)] or Asp [Cdc37(13SD)]. As shown in Fig. Fig.2C,2C, CK2 phosphorylated Cdc37(WT) (lane 1) but not Cdc37(13SA) (lane 2) or Cdc37(13SD) (lane 3), indicating that Ser13 of Cdc37 is the sole phosphorylation site by CK2 in vitro.
What is the function of Cdc37?
Cdc37 is a kinase-associated molecular chaperone whose function in concert with Hsp90 is essential for many signaling protein kinases. Here, we report that mammalian Cdc37 is a pivotal substrate of CK2 (casein kinase II). Purified Cdc37 was phosphorylated in vitro on a conserved serine residue, Ser13, by CK2. Moreover, Ser13 was the unique phosphorylation site of Cdc37 in vivo. Crucially, the CK2 phosphorylation of Cdc37 on Ser13 was essential for the optimal binding activity of Cdc37 toward various kinases examined, including Raf1, Akt, Aurora-B, Cdk4, Src, MOK, MAK, and MRK. In addition, nonphosphorylatable mutants of Cdc37 significantly suppressed the association of Hsp90 with protein kinases, while the Hsp90-binding activity of the mutants was unchanged. The treatment of cells with a specific CK2 inhibitor suppressed the phosphorylation of Cdc37 in vivo and reduced the levels of Cdc37 target kinases. These results unveil a regulatory mechanism of Cdc37, identify a novel molecular link between CK2 and many crucial protein kinases via Cdc37, and reveal the molecular basis for the ability of CK2 to regulate pleiotropic cellular functions.
Where is Cdc37 recombinant?
For recombinant Cdc37 purification, BglII fragments that contain coding regions of Cdc37 were introduced into a BamHI site of pGEX-6P2 (Amersham Pharmacia) to construct glutathione S-transferase (GST)-Cdc37 fusion proteins. For the expression of Cdc37 in mammalian cells with an HA tag, the BglII fragments were introduced into a BglII site of pcDNA3-HA (30).
How does CHK2 help the body?
CHK2 and other proteins respond to the damage by halting cell division and assessing whether the cell is better off repairing the damage or self-destructing for the good of the body. This process ensures that cells with genetic damage or mutations don’t pass the “bad” DNA on to their descendants when they divide. Such mutations can be a first step toward cancer. Because it helps prevent cells from becoming cancerous, CHEK2 is known as a tumor-suppressor gene.
What type of cancer is Chek2?
CHEK2 mutations are found in a variety of cancer types, including breast, colon, prostate, kidney, thyroid, and other cancers, according to the National Institutes of Health. The mutations have also been found in some brain tumors and in osteosarcoma, a form of bone cancer.
How many copies of Chek2 are there?
Most individuals who carry a mutation in CHEK2 have one normal copy of the gene and one mutated copy. Because children inherit one copy of each gene from each of their parents, people with a CHEK2 mutation have a 50% chance of passing on the mutation to their children.
What is Chek2 gene?
What is CHEK2? August 26, 2019. Published: August 27, 2019. CHEK2 is a tumor-suppressor gene that protects cells from becoming cancerous. People who inherit mutations in the gene are at increased for certain types of cancer and may benefit from more frequent screening. Medically reviewed by Huma Rana, MD.
What happens when Chek2 is mutated?
When CHEK2 itself is mutated — when the DNA that constitutes the gene acquires an error — its ability to perform its assigned role is reduced. Without a properly functioning CHEK2 gene, cells lose a key restraint on their growth and may be a step closer to the unbridled division that is characteristic of cancer.
What is the name of the gene that makes the protein CHK2?
CHEK2 is the abbreviated name of the gene called checkpoint kinase 2 (gene names are written in italics). The gene provides cells with instructions for making a protein known as CHK2, which becomes active when DNA within the cell is damaged or strands of DNA break.
Can Chek2 cause breast cancer?
The risk of breast cancer in women with a CHEK2 mutation is believed to be at least double that of a woman without such a mutation. Because of this increase, women with the mutation are advised to have more intensive breast screenings.
List of Modifiers
- Modifiers can only be used in the correct scope. When using modifier in wrong scope, it will display as NONE in tooltip and/or will do absolutely nothing (though some modifier displayed as NONE may actually apply its effect): 1. Character: Character modifiers are attached to characters and modify their personal or state abilities, their behavior (f...
Custom Modifiers
- Custom modifiers can be defined in common/modifier_definitions. They are based on an hardcoded convention on their name, similarly to the sympathy_<religion>modifier, which works for any custom religion, not only vanilla religions. They are restricted to the following entities: 1. Special units: 1.1. <special_unit>: defines the modifier providing the troop itself. E.G., "horse_arc…
Static Modifiers
- Static modifiers are global modifiers (character, province, or unit), and defined in /common/static_modifiers.txt Some of these modifiers are referenced from the code.
Event Modifiers
- Event modifiers are either: 1. character modifiers 2. province modifiers 3. holding modifiers (since patch 2.4) They are stored under common/event_modifiers/and grouped and referenced by a name. In addition to their modifier properties, they also have: 1. an optional is_visiblecondition block, to decides if the viewer can see this trait on holder (default is yes). ROOT is the viewer, FR…
Triggered Modifiers
- Triggered modifiers are similar to character event modifiers, except that they do not need to be attached or detached by script: depending on conditions they will automatically be applied or removed. For performance reasons, they only apply to playable characters (counts or above). As they are evaluated every day for every landed character in existence, these are very resource inte…
Religion Modifiers
- Religion modifiers impact the moral authority of a religion.They are stored under common/religion_modifiers/. Example: Religion modifiers can be attached via event with the religion_authoritycommand:
Society Modifiers
- The equivalent of religious moral authority for societies is influence. They are stored under common/event_modifiers/. They can also be capped via static modifier's static_modifier_cap = 10. Society modifiers are attached via event with add_society_modifiercommand.
Opinion Modifiers
- Opinion modifiers modify the relationsbetween two characters.They are somehow similar to the opinion_xxx character modifiers, but apply to a single character, rather than a group of character (clergy, mayors, ...). In addition they can contain extra information, such as cause for imprisonment.They are stored under common/opinion_modifiers/. In patch 2.1.5some hardcode…
Command Modifiers
- These modifiers apply only to the command_modifier clause of traits.They are multiplied by the number of martial points times COMMAND_MODIFIER_MARTIAL_MULTIPLIER = 0.05 For instance: