The key difference between JAK1 JAK2 and JAK3 is that JAK1 is essential for signaling of certain type I and type II cytokines while JAK2 is essential for signaling of type II cytokine receptor family, GM-CSF receptor family, gp130 receptor family, and single-chain receptors. Meanwhile, JAK3 is essential for signaling of type I receptors that use the common gamma chain (γc).
Janus Kinase (JAK or Jaks) is a family of intracellular non-receptor protein tyrosine kinases. They are comparatively large proteins comprising more than 1000 amino acids. Jaks are important for cell growth, survival, development, and differentiation of a variety of cells but are critically important for immune cells and hematopoietic cells. There are four members in the Jak family as Janus kinase 1 (Jak1), Janus kinase 2 (Jak2), Janus kinase 3 (Jak3), and Tyrosine kinase 2 (Tyk2). Jak1, Jak2, and Tyk2 are expressed ubiquitously in mammals while Jak3 is primarily expressed in hematopoietic cells. Tofacitinib is a selective inhibitor for JAK1 for JAK3, while baricitinib is selective for JAK1 and JAK2.
CONTENTS
1. Overview and Key Difference
2. What is JAK1
3. What is JAK2
4. What is JAK3
5. Similarities Between JAK1 JAK2 and JAK3
6. Side by Side Comparison – JAK1 vs JAK2 vs JAK3 in Tabular Form
7. Summary
What is JAK1?
JAK1 is one of the four members of the Jak family. It is a human tyrosine kinase protein which is essential for certain type I and type II cytokines. Moreover, Jak1 is important for transducing a signal by type I (IFN-α/β) and type II (IFN-γ) interferons, and members of the IL-10 family via type II cytokine receptor. Likewise, Jak1 plays a vital role in initiating responses to multiple major cytokine receptor families. Absence of Jak1 is lethal to mice.
Figure 01: JAK1
What is JAK2?
Janus kinase 2 or JAK2 is another member of Jak family which is a non-receptor tyrosine kinase. Gene JAK2 codes for JAK2 protein. Jak2 mediates signals from type II cytokine receptor family, GM-CSF receptor family, gp130 receptor family, and single-chain receptors. JAK2 lacks Src homology binding domains (SH2/SH3). But it contains up to seven JAK homology domains (JH1-JH7). These two features are helpful to distinguish JAK2 from the other three members.
Figure 02: JAK2
Loss of JAK2 is lethal to mice. Mutations in JAK2 gene is associated with several disorders including polycythemia vera, essential thrombocythemia, and myelofibrosis and other myeloproliferative disorders.
What is JAK3?
KAK3 is the third member of Jak family and is coded by JAK3 gene. JAK3 is important for signaling the type I receptors that use the common gamma chain (γc). JAK3 gene is expressed in hematopoietic and epithelial cells and produces JAK3 proteins. Jak3 deficiency results in severe lymphopenia in mice and humans.
Figure 03: JAK3
JAK3 functions are mainly restricted to lymphocytes. Hence, JAK3 inhibitors are attractive as a treatment for different types of autoimmune diseases. Mutations occurred in JAK3 gene cause severe combined immunodeficiency disease and leukemia.
What are the Similarities Between JAK1 JAK2 and JAK3?
- JAK1, JAK2 and JAK3 are JAK isoforms.
- They are intracellular non-receptor protein tyrosine kinases.
- In fact, they are large proteins.
- Jaks are highly conserved, and JAK isoforms are non-redundant.
- Loss of JAK1, JAK2 and JAK3 is lethal to mice.
- JAK inhibitors are medications used to inhibit the activity of JAK1, JAK2 and JAK3.
- Mutations in genes coding for JAK1, JAK2 and JAK3 cause disorders, including many bone marrow disorders, blood cancers, and autoimmune diseases.
What is the Difference Between JAK1 JAK2 and JAK3?
JAK1 is a member of Jak family which is essential for signaling of certain type I and type II cytokines. Whereas, JAK2 is a member of Jak family which is essential for signaling of type II cytokine receptor family, GM-CSF receptor family, gp130 receptor family, and single chain receptors. Meanwhile, JAK3 is the third member of Jak family which is essential for signaling of the type I receptors that use the common gamma chain (γc). So, this is the key difference between JAK1 JAK2 and JAK3. JAK1 gene codes for Jak1 while JAK2 gene codes for Jak2 and JAK3 gene codes for Jak3.
The below infographic tabulates more differences between JAK1 JAK2 and JAK3.
Summary – JAK1 JAK2 vs JAK3
Jak proteins link the cytokine signaling from membrane receptors to signal transducers and activators of transcription (STAT) transcription factors. Therefore, Jaks are crucial proteins in signal transduction initiated by a wide range of membrane receptors, especially IFN alpha, beta and gamma receptors. Jaks are extensively studied due to their crucial roles in cancer and inflammation. The JAK family in mammals contains four isoforms as JAK1, JAK2, JAK3, and TYK2. The key difference between JAK1 JAK2 and JAK3 is that JAK1 is essential for signaling of certain type I and type II cytokines while JAK2 is essential for signaling of type II cytokine receptor family, GM-CSF receptor family, gp130 receptor family, and single-chain receptors and JAK3 is essential for signaling of type I receptors that use the common gamma chain (γc).
Reference:
1. Ghoreschi, Kamran, et al. “Janus Kinases in Immune Cell Signaling.” Immunological Reviews, U.S. National Library of Medicine, Mar. 2009, Available here.
2. “Janus Kinase.” Wikipedia, Wikimedia Foundation, 19 Nov. 2020, Available here.
Image Courtesy:
1. “Protein JAK1 PDB 3EYG” By Pleiotrope – Own work (Public Domain) via Commons Wikimedia
2. “Protein JAK2 PDB 2b7a” By Emw – Own work (CC BY-SA 3.0) via Commons Wikimedia
3. “JAK3 signal transduction” By Rayray7 – Own work (CC BY-SA 3.0) via Commons Wikimedia