JAK3 Gene Editing

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JAK3 Gene Editing    

JAK3 is a protein coding gene. The protein encoded by this gene is a member of the Janus kinase (JAK) family of tyrosine kinases involved in cytokine receptor-mediated intracellular signal transduction. Other members of the Janus family include JAK1, JAK2 and TYK2. JAKs are conserved in domain structure, with an N-terminal FERM domain and a Src homology 2 (SH2)-like domain, followed by a pseudokinase domain (JAK homology 2, JH2) and a tyrosine kinase domain (JH1). They are relatively large kinases of approximately 1150 amino acids with apparent molecular weights of 120-130 kDa. It is predominantly expressed in immune cells and transduces a signal in response to its activation via tyrosine phosphorylation by interleukin receptors. Non-receptor tyrosine kinase is also involved in various processes, such as cell growth, development, or differentiation.

JAK3 mediates essential signaling events in both innate and adaptive immunity, and plays a crucial role in hematopoiesis during T-cells development. In the cytoplasm, it plays a pivotal role in signal transduction via its sole association with type I receptors sharing the common subunit gamma (γc), such as IL2R, IL4R, IL7R, IL9R, IL15R and IL21R, which regulate development and activation of lymphoid lineage cells. In IL-2 receptor (IL-2R) signaling, as well as cytokine signaling, when ligand binds to extracellular domain of cell surface receptors β or γ chains, JAK1 and JAK3 phosphorylates specific tyrosine residues of receptor subunits on the cytoplasmic tails, creating docking sites for signal transducers and activators of transcription (STATs) proteins. Then, for example, STAT5A and STAT5B are recruited. Subsequently, JAK3 phosphorylates the STATs proteins. Phosphorylated STATs then form homodimer or heterodimers, and translocate to the nucleus to activate transcription of specific target genes in a cytokine-specific fashion.

TypeSubgroupCytokine ReceptorJAK Kinase
type I receptorshomodimericEPO, TPO, GH, G-CSFJAK2
uses common beta chain (CSF2RΒ)IL-3, IL-5, GM-CSFJAK2
uses gp130 chainIL-6, IL-11JAK1, JAK2, Tyk2
uses common gamma chain (γc)IL-2, IL-4, IL-7, IL-9, IL-15, IL-21JAK1, JAK3
type II receptors IFN-α, IFN-β, IFN-γJAK1, JAK2, Tyk2

Table 1 Some cytokine receptors and their involvement with JAK kinases (O'Shea JJ et. al, 2005)

Mutations in JAK3 gene are associated with autosomal SCID (severe combined immunodeficiency disease). JAK3 mutations are also found in patients of T-cell acute lymphoblastic leukemia (T-ALL), acute megakaryoblastic leukemia, T-cell prolymphocytic leukemia, and juvenile myelomonocytic leukemia and natural killer T-cell lymphoma (NK/T-lymphoma). JAK plays a central role in the control of lymphopoiesis. The pseudokinase domain (JAK homology 2, JH2) of JAK3 shows significant sequence homology with classical protein kinases but several conserved functional residues or motifs are missing or altered. JAK JH2s is of particular interest as approximately half of clinical JAK3 mutations cluster into it. Recent studies have focused on tyrosine kinases as potential targets for the treatment of Rheumatoid arthritis (RA), which is a chronic, systemic disease characterized by persistent inflammatory synovitis. Among them, inhibitors specific for the JAK family are, so far, the most efficacious in treating RA. Selective JAK3 inhibition should be sufficient for immunosuppression without causing effects outside the immune system.

JAK3 Gene Editing JAK3 Inhibition Mechanism (Warren J Leonard et al., 2016)

Genome Editing is revolutionizing biomedical research, due to its high efficiency, ease-of-use, and relatively low cost. CRISPR/Cas9 PlatformCB, a global biotechnological company specializing in gene editing, is dedicated to offering comprehensive CRISPR/Cas9 gene editing products and services for academic research, biotech research and pharmaceutical drug discovery. With products for CRISPR-Cas9 clones, validation and screening kits, pre-made transfected stable cell lines, and more for precision genome editing, our complete solutions for genome editing provide you with a wealth of tools to help you every step of the way in your genome editing workflow.

  • Gene Editing Cell Line Generation

Our specialists will provide with helpful tips on designing and using gRNA and Cas9 constructs, CRISPR libraries, designing KO mammalian cell lines, and more!

ServiceDetailsCell Line Options *
Knockout Cell Line ServiceSingle gene knockout cell lineAvailable for any transfection-suitable cell lines, including A549, CHO-K1, HEK293, HEK293T, HCT116, MCF7, MDCK, U937, RPMI 8866, HT-29, MDA-MB-231, 4T1, A20, etc.
Transfection-based
Customer specifies gene/locus region and cell line of interest*
Customized Knockout Cell Line ServiceSingle or multiplex genes editing knockout cell lineAny cancer cell line
Transfection/Lentivirus/Ribonucleoprotein-based
Customer specifies gene/locus region and cell line of interest*

* It is preferred that customers provide their own cell lines, despite available cell lines can be purchased by Creative Biogene for an additional fee.

Related Details

Guide RNA Design:

Our expert scientists from Creative Biogene will optimize your guide RNA sequence for maximized efficiency and minimal off-target effects using best design algorithms.

Materials Needed from Clients:

Target gene name.

Target gene sequence, if the whole genome sequence is unavailable.

Quality Control

Sequence Chromatogram

Quality Assurance Certificate

Quantitative RT-PCR Validation (Optional)

Western Blot Validation (Optional)

Deliverables

Knockout cell lines validated by sequencing

Delivery Time

Starting from 4 weeks

  • Gene Editing Animal Model Generation
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Gene Knockout Mouse GenerationConditional Knockout Mouse
Conventional Knockout Mouse
Point Mutation Mouse
Starting from 4 weeks
Gene Knockin Mouse GenerationCRISPR/Cas9 Knockin Mouse
Rosa26 Knockin Mouse
Starting from 4 weeksAny other target gene knockin mouse generation
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Starting from 4 weeksAny other animal models according to our client's requirements

CRISPR/Cas9 PlatformCB is devoted to providing the best gene editing services to accelerate the achievement of your research goals. We are committed to providing the most reliable and effective research services and products with excellent quality management and quality assurance capacity. If you have any questions, please feel free to contact us.

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The products and the reagents generated from these services shall be only used as tools for research purposes, and shall exclude (a) any human or clinical use, including, without limitation, any administration into humans or any diagnostic or prognostic use, (b) any human germline modification, including modifying the DNA of human embryos or human reproductive cells, (c) any in vivo veterinary or livestock use, or (d) the manufacture, distribution, importation, exportation, transportation, sale, offer for sale, marketing, promotion or other exploitation or use of, or as, a testing service, therapeutic or diagnostic for humans or animals.

References

  1. Leonard WJ, O'Shea JJ (1998). "Jaks and STATs: biological implications". Annual Review of Immunology. 16: 293-322.
  2. Ghoreschi K, Laurence A, O'Shea JJ. Janus kinases in immune cell signaling. Immunol Rev. (2009) 228:273-87. doi: 10.1111/j.1600-065X.2008.00754.
  3. Juuli Raivola et al. Hyperactivation of Oncogenic JAK3 Mutants Depend on ATP Binding to the Pseudokinase Domain. Front. Oncol. 2018 doi: 10.3389.
  4. Vicente C, Schwab C, Broux M, Geerdens E, Degryse S, Demeyer S, Lahortiga I, Elliott A, Chilton L, La Starza R, Mecucci C, Vandenberghe P, Goulden N, Vora A, Moorman AV, Soulier J, Harrison CJ, Clappier E, Cools J (October 2015). Targeted sequencing identifies associations between IL7R-JAK mutations and epigenetic modulators in T-cell acute lymphoblastic leukemia. Haematologica. 100 (10): 1301-10.
For research use only. Not intended for any clinical use.

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