Biology and significance of the JAK/STAT signalling pathways

Abstract

Since its discovery two decades ago, the activation of the JAK/STAT pathway by numerous cytokines and growth factors has resulted in it becoming one of the most well studied intracellular signalling networks. The field has progressed from the identification of the individual components, to high-resolution crystal structures of both JAK and STAT, and an understanding of the complexities of the molecular activation and deactivation cycle which results in a diverse, yet highly specific and regulated pattern of transcriptional responses. While there is still more to learn, we now appreciate how disruption and de-regulation of this pathway can result in clinical disease and look forward to adoption of the next generation of JAK inhibitors in routine clinical treatment.

IL-4, JAK-STAT signaling, and pain

“…39 JAK-STAT regulation thereby aims at controlling the magnitude and duration of cytokine signaling and includes different mechanisms such as receptor internalization by vesicles and subsequent receptor degradation, dephosphorylation by phosphatases (PTPs), and posttranslational modifications of STAT proteins. Furthermore, there are two classes of endogenously expressed negative regulators.…”

“…39 The route starts with the binding of the ligand to its receptor, which dimerizes followed by the association and autophosphorylation of usually two out of four known JAK proteins (JAK1, JAK2, JAK3, and TYK2) and the subsequent docking of certain STAT proteins comprising a family of seven members (STAT1, STAT2, STAT3, STAT4, STAT5A/B, and STAT6). Once bound to the receptor, SH2 domains of the STATs connect to the phosphotyrosines on the tail of the receptor and STAT phosphorylation by JAKs occurs.…”

Growth hormone (GH) modulation of Epidermal growth factor (EGF) signalling in human mammary epithelial cells

“…As mentioned above, in mammary gland basically STAT-5a and -5b are expressed (Liu et al, 1995;Kiu and Nicholson, 2012). STAT-5a is needed for functional development of mammary tissue.…”

“…They all contain an oligomerization domain, a DNA binding domain and a Src homology 2 domain (SH2) (Quesnelle et al, 2007). In the mammary gland STAT-5a and STAT-5b are mostly expressed (Liu X et al, 1995;Kiu and Nicholson, 2012). STAT-5a and -5b are encoded by two linked genes and share over 90% identity with two related sequences (Azam et al, 1995) and differ only at their carboxy termini.…”

Comment on "Acute lymphoblastic leukemia and adiponcosis" by M. Bifulco and AM Malfitano

“…It has been shown that obesity induces growth factor overexpression that induces cancer growth, and enhances further cancer growth due to the higher percentage of white adipose tissue (that is orchestrated by enhanced lipid signaling that accelerates the JAK-STAT and NF kappa beta pathway). 11 Obesity may further enhance cancer growth by the influence of immune responses, inflammatory responses, insulin resistance and adipokine expression. 12 Also, in pediatric solid tumors with overgrowth syndromes, the influence of endogenous growth factor exposure has been shown to facilitate the hyperproliferative processes of oncogenesis.…”