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JAK-STAT pathway: Testicular development, spermatogenesis and fertility
Published in Rajender Singh, Molecular Signaling in Spermatogenesis and Male Infertility, 2019
In JAK-STAT signaling, nonreceptor tyrosine kinase is the main class of receptors. These are single-membrane receptors with no intrinsic tyrosine kinase activity. Their intracellular cytoplasmic tails are associated with JAK, which gets phosphorylated on ligand binding and recruits STAT for further extending pathway function. In mammals, the subfamilies are gp130 family receptor, IL-2 family receptors, gp140 family receptors and growth hormone family receptors (10,11). In Drosophila, Domeless is the only known receptor that is encoded by the Dome gene (20) and also named as Master of Marelle (MOM) by another group (21). These nonreceptor tyrosine kinase receptors have a cytoplasmic membrane proximal domain through which they associate with tyrosine kinase-JAK (26). Domeless is a membrane-associated protein. Its extracellular domain consists of five fibronectin type III domains (FNIII). Out of these, two show similarity to the cytokine binding module of vertebrate cytokine receptor family I, which includes four conserved cysteine residues in the N-terminal domain and an incomplete WSXWS motif in the C-terminal domain (20) (Figure 15.2).
Protein Phosphorylation
Published in Enrique Pimentel, Handbook of Growth Factors, 2017
The tec gene, which encodes a putative tyrosine kinase, was detected by screening of a murine liver cDNA library with the tyrosine kinase domain of the v-fps oncogene as a probe.319 The tec cDNA clone contains an ORF encoding a polypeptide of 527 amino acids with a calculated molecular weight of 61,556 Da. The carboxyl-terminal portion of the Tec protein exhibits a high degree of homology to the catalytic domain of other tyrosine kinases, especially with the v-Abl and v-Src oncoproteins, and contains a single putative autophosphorylation site. The Tec protein is likely to be a nonreceptor tyrosine kinase. The tec gene is expressed mainly in liver. High levels of tec expression were found in two human hepatocellular carcinoma cell lines.
Molecular Mechanisms of Endocrine Disruption in Estrogen Dependent Processes
Published in Rajesh K. Naz, Endocrine Disruptors, 2004
Robert M. Bigsby, Minerva Mercado-Feliciano, Josephine Mubiru
It was suggested nearly 30 years ago that estrogen acted not only at the nuclear receptor level but also through a membrane-bound receptor to induce rapid intracellular changes in second messenger molecules such as Ca2+ and cAMP.113,114 More recently, several potential molecular mechanisms have been described for estrogen action at the membrane or through pathways involving growth factor receptors (see reviews).115–118 These pathways are depicted in Figure 7.3. Accordingly, estrogens have been shown to interact directly with G-protein coupled receptors (GPCR) to stimulate activation of membrane-associated proteases, such as matrix metalloprotease, that cause release of membrane-bound growth factor peptides, which in turn activate members of the erbB family of growth factor receptors. Activation of the GPCR also has the effect of increasing adenylate cyclase activity, increasing cAMP, and activating protein kinase A (PKA). Alternatively, estrogen may interact directly with erbB proteins, thereby activating the intracellular signaling mechanisms. Other research has shown that ligand activated ERα can interact with non-receptor tyrosine kinase, c-Src, to stimulate changes in cell shape and motility. The mitogen-activated protein kinases (MAPK) ERK-1 and ERK-2 can phosphorylate ERα, thereby enhancing its transactivation function. Phosphorylated ERα also interacts with the intermediary protein, Shc, allowing it to form a complex with Grb-2 and Sos; this complex may bind and activate the Ras/Raf complex. Each of these pathways leads to physiological changes within the cell and to transcriptional activation through activation of ER and other transcription factors such as Elk1, AP-1 (Jun/Fos), and CREB. These pathways are known to impinge on cellular proliferation, apoptosis, and differentiation.
Topical and systemic JAK inhibitors in hand eczema – a narrative review
Published in Expert Review of Clinical Immunology, 2023
Adam Zalewski, Jacek C. Szepietowski
First described in the early 1990s, Janus-activated kinases (JAK) are proteins composed of two domains – one performing the kinase activity, and another – negatively regulating the activity of the first domain. They are defined as an intracellular, non-receptor tyrosine kinase [41]. There are four representatives of the JAK family: JAK1, JAK2, JAK3, and tyrosine kinase 2 (TYK2) [42–45]. STAT proteins are a group of latent cytoplasmic intracellular transcription factors that mediate many processes of cellular immunity, cell growth, and differentiation or apoptosis. Seven types of STATs can be distinguished: STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B, and STAT6. Their primary activation occurs with the involvement of receptor-associated JAK-kinases [46,47]. STAT signaling cascade is an example of a direct pathway in which STAT protein is bound to receptors at the surface of the cell and translocated toward nucleus, where they act as gene activating transcription factors [46].
Fedratinib-induced orbital inflammation
Published in Orbit, 2022
John Y. Lee, Ryan A. Gallo, Daniel M. Vu, Apostolos G. Anagnostopoulos, Andrew J. Rong
Mutations in the non-receptor tyrosine kinase JAK2 are most prevalent in MPNs and occur in 50–60% of patients with MF.5 The unrestricted clonal expansion exhibited in MF is attributed to constitutive upregulation of JAK2 and downstream hypersensitivity of hematopoietic stem cells to activating cytokines.4 Thus, inhibition of this kinase with drugs like ruxolitinib and fedratinib alleviate symptoms of disease progression. In particular, fedratinib demonstrates JAK2 specificity and has been effective in ruxolitinib-resistant populations.6 With its recent FDA approval in 2019, a comprehensive side effect profile for fedratinib has yet to be established, and eye-related findings have not been reported.6,7 Nevertheless, its sister drug ruxolitinib has been linked to a case of bilateral toxoplasmosis retinitis thought to be caused by increased immune susceptibility.8
Acalabrutinib: a bruton tyrosine kinase inhibitor for the treatment of chronic lymphocytic leukemia
Published in Expert Review of Hematology, 2022
Anna Wolska-Washer, Tadeusz Robak
Unlike normal B lymphocytes, it has been demonstrated that CLL cells rely on increased constitutive activation through their B-cell receptor (BCR) [3]. The BCR-induced hyperresponsiveness of CLL cells may be the main driving force in the disease, with this effect being supplemented by other abnormalities (TP53 disruption) during the natural course of the disease [3]. Therefore, inhibition of BCR signaling in CLL has become the method of choice in tackling this disease. The benefits of the non-chemotherapeutic approach have been investigated in several trials using BCR signaling inhibitors, namely Bruton tyrosine kinase (BTK) and PI3-kinase (PI3k) inhibitors, or B cell lymphoma 2 (BCL2) antagonist, both in monotherapy and combined with monoclonal antibodies [4–7]. This approach was first applied in patients ineligible for chemoimmunotherapy due to comorbidities or age, but has also been approved as an effective option where classical chemoimmunotherapy has failed or in older unfit patients, especially in cases with dismal prognosis (TP53 disruption, unmutated IGHV) [1,8]. BTK is a cytoplasmic non-receptor tyrosine kinase that belongs to the TEC-family of kinases. It is expressed in all hematopoietic cells, especially B lymphocytes, mast cells, and macrophages, but also in platelets [9,10]. It is believed to be play a role in the signaling machinery from the BCR.