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Protein Phosphorylation
Published in Enrique Pimentel, Handbook of Growth Factors, 2017
The hck gene was isolated and characterized by screening a cDNA library from mitogen-stimulated human leukocytes using a murine lck probe.276,287 Structural analysis of the human hck promoter has been reported.288 The gene encodes a 505-residue polypeptide of 59 kDa, termed p59hck or Hck, which is closely related to the product of the lck gene and possesses tyrosine kinase activity. The hck gene is a member of the src family and its product is expressed mainly in cells of hematopoietic origin, especially in terminally differentiated granulocytes. Increased hck gene expression occurs in the granulocytic differentiation of human myeloid leukemia cell lines.219 Expression of hck is induced by LPS in human macrophages, which depends on the presence of an LPS-responsive element located within the hck promoter.289,290 In contrast, the fgr gene, which is structurally related to hck, is downregulated during macrophage activation. The Hck protein is likely to be a cell surface membrane protein and may be a receptor for an unidentified hematopoietic growth factor. Hck may assist in regulating signal transduction in myeloid cells. The hck gene has been mapped to human chromosome region 20ql 1-12, which is not far from the c-src locus.
Dasatinib: A Dual ABL and SRC Inhibitor
Published in Jorge Cortes, Michael Deininger, Chronic Myeloid Leukemia, 2006
Alfonso Quintás-Cardama, Hagop Kantarjian, Jorge Cortes
Src kinases represent a family of nine structurally homologous nonreceptor intracellular tyrosine kinases (Src, Fyn, Yes, Blk, Yrk, Fgr, Hck, Lck, and Lyn) that regulate signal transduction pathways involved in cell growth, differentiation, and survival (4). The expression of some Src kinases is ubiquitous, whereas others display more tissue-specific patterns of expression. For example, Hck, Lyn, Fgr, Lck, and Blk are strictly restricted to hematopoietic cells (4). Furthermore, Hck is circumscribed to myeloid cells and B-lymphocytes, whereas Lyn is expressed in myeloid cells, B-lymphocytes, and NK cells (4). In addition, multiple domains of Bcr-Abl interact with Hck and Lyn leading to their activation, and experiments with Src dominant-negative mutants suggest that Src kinases play a role in proliferation of BCR-ABL–expressing cell lines (4–6). However, neither the formation of the Hck-Bcr-Abl complex nor the Bcr-Abl–mediated activation of Hck is dependent on the Abl kinase activity (7). Overexpression of Src family of kinases has also been implicated in BCR-ABL–mediated leukemogenesis and, in some cases, in imatinib resistance (8–11). Paired samples from patients with CML obtained before and after imatinib failure suggested that overexpression of Hck and Lyn occurred during CML progression to blast phase (BP), suggesting that acquired imatinib resistance may be mediated by overexpression of Src kinases in at least some patients (9). Activation of Src kinases may promote phosphorylation of BCR-ABL and interaction with Grb2 (6,7). In addition, Abl has significant sequence homology with Src and, in its active configuration, it bears a remarkable structural resemblance with Src family kinases. ATP-competitive compounds originally developed as Src inhibitors frequently have potent inhibition of Abl kinase due to the striking resemblance between the catalytically active state of both protein kinases (12). On the basis of the structural similarity between Abl and Src and their proposed critical role in the pathogenesis of CML, it could be hypothesized that small molecule inhibitors with activity against both ABL and Src may have increased activity in CML compared to that of more selective inhibitors, such as imatinib that has negligible activity against Src kinases. This may be at least partially due to the fact that in the inactive configuration, the only one to which imatinib can bind, Abl is much less structurally similar to Src.
Ibrutinib plus rituximab for the treatment of adult patients with Waldenström’s macroglobulinemia: a safety evaluation
Published in Expert Opinion on Drug Safety, 2021
Magdalini Migkou, Despina Fotiou, Maria Gavriatopoulou, Meletios Athanasios Dimopoulos
In 2012, whole genome sequencing of CD19+ bone marrow cells led to the identification of the MYD88 somatic mutation which involves an amino-acid change from leucine to proline (L265P) [13]. MYD88 is involved in the signal transduction pathways hyperactivating nuclear factor kappa B (NFκβ) and mitogen-activated protein kinase (MAPK) and its activation induces tumorigenesis and increased cell survival [13]. BTK forms a complex with the mutated MYD88 and is constitutively activated. Ibrutinib therefore activates apoptosis, inhibits DNA replication, and blocks prosurvival signaling pathways. It inhibits HCK and causes inactivation of downstream transcription factors and cytokine/chemokine downregulation. [23]. (Table 2 summarizes main pharmacokinetic properties)
Suppression of hematopoietic cell kinase ameliorates the bone destruction associated with inflammation
Published in Modern Rheumatology, 2020
Yusoon Kim, Mikihito Hayashi, Takehito Ono, Tetsuya Yoda, Hiroshi Takayanagi, Tomoki Nakashima
NRTKs are cytoplasmic enzymes that transfer phosphate groups to tyrosine residues on protein substrates. NRTKs play a crucial role in various biological functions, including cell proliferation and immune reactions. It has been shown that several NRTKs, including Src, spleen tyrosine kinase (Syk), Bruton's tyrosine kinase (Btk) and Tec, are essential for the regulation of osteoclast differentiation and function [1,6]. However, the relationship between NRTKs and inflammation-induced osteoclastogenesis is still incompletely understood. To identify the NRTKs activated during osteoclastogenesis in the presence of pro-inflammatory cytokines, we investigated microarray-based gene expression profiles in the bone marrow-derived monocyte/macrophage precursor cells (BMMs) stimulated with RANKL and TNF-α. As a result, we found a selective induction of hematopoietic cell kinase (Hck) expression upon RANKL and TNF-α stimulation. Hck, a member of the Src family of kinases (SFKs), is known to be expressed in B and myeloid lineage cells and is involved in several types of hematological malignancies and pro-inflammatory responses [7]. In this study, we examined the effect of Hck inhibition on osteoclastogenesis under inflammatory condition using the potent Hck inhibitor A-419259 trihydrochloride in vitro and evaluated the therapeutic effect of A-419259 on LPS-induced inflammatory bone destruction in vivo.
Neochlorogenic acid: an anti-HIV active compound identified by screening of Cortex Mori [Morus Alba L. (Moraceae)]
Published in Pharmaceutical Biology, 2021
Jing Li, Lu Dou, Shuangfeng Chen, Honghao Zhou, Fangzheng Mou
In our research results, the four genes HCK, EGFR, SRC, and PDPK1 may be potential targets through which neochlorogenic acid inhibits HIV infection in humans. HCK protein is a member of the Src family of non-receptor tyrosine kinases, which is preferentially expressed in myeloid and B lymphoid haematopoietic cells (Moarefi et al. 1997). Nef is a multifunctional pathogenic protein of HIV-1, and its interaction with the Src tyrosine kinase Hck, which is highly expressed in macrophages, is related to the development of AIDS (Suzu et al. 2005; Hiyoshi et al. 2008). We speculate that neochlorogenic acid may competitively bind HCK protein, thereby inhibiting Nef protein function. Few studies have examined EGFP and HIV, and they have mainly focussed on mutations (Crequit et al. 2016; Walline et al. 2017; Liu et al. 2019). Kaposi sarcoma (KS) is the most common malignant tumour in HIV/AIDS. HIV-related exosomes increase the expression of HIV transactivator (TAR) RNA and EGFR in oral mucosal epithelial cells, thereby promoting Kaposi sarcoma-associated herpesvirus (KSHV) infection (Chen et al. 2020). Lin et al. (2011) found that the phosphorylation level of PDPK1 is closely associated with the expression of p300 protein, which regulates the function of the HIV-1-encoded RNA-binding protein Tat. The above results all show that our prediction results are fairly reliable. In addition, we found that neochlorogenic acid can bind the RT of HIV-2, thus suggesting that neochlorogenic acid may have a favourable inhibitory effect on HIV-2. This result further shows that neochlorogenic acid is a potent inhibitor of HIV-1 virus replication.