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Intracellular signalling pathways

Cytokines operate in the extracellular environment, stimulating cells via cell surface receptors.1 For the cell to act on the cytokine signal, an intracellular signal must reach the nucleus and stimulate gene transcription.1 There are a number of intracellular pathways that are known to transmit signals from cytokine receptors at the cell surface to the cell nucleus (see diagram). Many integral membrane-bound cytokine receptors have intrinsic enzymatic activity and can trigger transmission of signals within the cell on their own. However, some receptors (type I and II cytokine receptors) lack this intrinsic enzymatic activity and must associate with cytoplasmic kinases, known as Janus kinases (JAKs), to initiate signal transmission within the cell.

AK pathways: Janus kinases (JAKs) are involved in signalling by multiple different cytokines and are key mediators in the activation of the inflammatory response. JAKs associate with intracellular messenger proteins called STATs (signal transducers and activators of transcription) to transmit signals from cell surface receptors to the nucleus. The pathway is therefore also referred to as the JAK-STAT pathway. JAK-STAT signalling (primarily via JAK2) is also known to be important in haematopoiesis.2

MAPK pathways: Mitogen-activated protein kinases (MAPK) are a family of intracellular proteins, including ERK, p38 and JNK, which are involved in regulating a variety of cellular activities including proliferation, differentiation, survival, and death. MAPK pathways are implicated in the development of various types of cancer (via ERK) and neurodegenerative diseases (via p38 or JNK).3

SYK pathways: Spleen tyrosine kinase (SYK) and its homologue ZAP70 are known to relay adaptive immune receptor signalling but are also found in insects, suggesting a role in innate immunity as insects do not have an adaptive immune system. SYK and ZAP70 are also known to mediate diverse functions related to cellular adhesion, bone metabolism, vascular development and activation of platelets.4

NF-κB pathways: The nuclear factor-kappa B (NF-κB) family of transcription factors are crucial in signalling related to various biological processes, including immune response, inflammation, cell growth and survival, and development. Abnormal NF-κB signalling is implicated in the pathogenesis of a variety of autoimmune diseases and cancers.5

PI-3K pathways: Phosphoinositide 3-kinases (PI-3K) phosphorylate membrane-bound lipids to produce specific molecular messengers within the membrane, which stimulate complex signalling pathways to transfer a signal to the nucleus. PI-3K pathways are always activated in parallel with other intracellular signalling pathways, so the precise effects of their activation are difficult to define. However, certain Class I PI-3Ks are known to be involved in T- and B-cell development and differentiation and chemotaxis of immune cells to the site of inflammation.6

JAK pathways are key mediators in the activation of the inflammatory response

Adapted from Murphy K, Weaver C. 2016.1

JAK is a family of non-receptor protein tyrosine kinases (PTKs) located in the cytoplasm of cells, rather than on the cell surface. When activated, JAKs stimulate a cascade involved in the production of pro-inflammatory cytokines. Overactivation of JAK can lead to inflammation and tissue destruction.2,7

The JAK family consists of 4 members: JAK1, JAK2, JAK3, and TYK2 (tyrosine kinase 2):2,8

  • JAK1, JAK2, and TYK2 are ubiquitously expressed
  • JAK3 (which pairs with JAK 1) is predominately expressed in haematopoietic cells

Each JAK protein has specificity for a different set of cytokine receptors.8

  • ​​​​​​​The function of the JAK protein is linked to the function of the cytokines that bind the receptors:​

JAK dimers and STAT combinations

JAK subunits must form dimers in order to transmit the signal from the cell surface receptor. The subunits can form either homodimers (e.g. JAK2/JAK2) or heterodimers (e.g. JAK1/JAK3).

Each JAK pairing has specificity for a different set of cytokines.9

Each JAK dimer transfers its signal to the nucleus through activation of one or more members of the STAT family of transcription factors. There are seven STAT family members: STAT 1, 2, 3, 4, 5a, 5b and 6. The precise combinations of JAKs and STATs involved in signalling differs between cytokine receptors.1,2,9,10

*Type II cytokine receptors such as those for IL-10, Il-19, IL-22 as well as gp130 subunit sharing receptors for IL-6 and IL-11 mainly signal through JAK 1, but also associate with JAK 2 AND TYK2.2



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Prescribing Information:

XELJANZ (tofacitinib citrate) Prescribing Information -  5mg and 10mg film-coated tablets
​​​​​​​XELJANZ (tofacitinib citrate) Prescribing Information -  11mg prolonged release tablets

References:
  1. Murphy K, Weaver C. Janeway’s Immunobiology. 9th ed. New York, NY: Garland Science, Taylor & Francis Group, LLC; 2016.
  2. Ghoreschi K, et al. Janus kinases in immune cell signalling. Immunol Rev 2009; 228(1): 273–287.
  3. Kim EK, Choi EJ. Pathological roles of MAPK signaling pathways in human diseases. Biochim Biophys Acta 2010;1802:396-405.
  4. Mócsai A, et al. The SYK tyrosine kinase: a crucial player in diverse biological functions. Nat Rev Immunol 2010;10(6):387–402.
  5. Park MH, Hong JT. Roles of NF-kB in cancer and inflammatory diseases and their therapeutic approaches. Cells. 2016;5(2):15.
  6. Hawkins PT, Stephens LR. PI3K signalling in inflammation. Biochim Biophys Acta 2015;1851:882-897.
  7. Smolen JS, Steiner G. Therapeutic strategies for rheumatoid arthritis. Nat Rev Drug Discov 2003; 2(6): 473–488.
  8. Pesu M, et al. Therapeutic targeting of Janus kinases. Immunol Rev 2008; 223: 132–142.
  9. Murray PJ. The JAK-STAT signaling pathway: input and output integration. J Immunol 2007; 178(5): 2623-2629.
  10. O’Sullivan LA, et al. Cytokine receptor signaling through the Jak-Stat-Socs pathway in disease. Mol Immunol 2007;44:2497-2506.​​​​​​​

    ​​​​​​​
    ​​​​​​​PP-XEL-GBR-2306. June 2021​​​​​​​

Announcement Title

XELJANZ Risk Minimisation Programme (RMP) materials, including a Patient Alert Card, Prescriber Checklists and a Prescriber Brochure are available from https://www.medicines.org.uk/emc/. Patients treated with XELJANZ should be given the Patient Alert Card.

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PP-PFE-GBR-2688. December 2020

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