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TEC family kinases in health and disease – loss‐of‐function of BTK and ITK and the gain‐of‐function fusions ITK–SYK and BTK–SYK

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The FEBS Journal
Authors:
Alamdar Hussain at COMSATS University Islamabad
Alamdar Hussain
Liang Yu at Karolinska Institutet
Liang Yu
Rani Faryal at Quaid-i-Azam University
Rani Faryal
Dara K. Mohammad at Salahaddin University - Erbil
Dara K. Mohammad
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Abstract

The TEC family is ancient and constitutes the second largest family of cytoplasmic tyrosine kinases. In 1993, loss-of-function mutations in the BTK gene were reported as the cause of X-linked agammaglobulinemia. Of all the existing 90 tyrosine kinases in humans, Bruton's tyrosine kinase (BTK) is the kinase for which most mutations have been identified. These experiments of nature collectively provide a form of mutation scanning with direct implications for the several hundred endogenous signaling proteins carrying domains also found in BTK. In 2009, an inactivating mutation in the ITK gene was shown to cause susceptibility to lethal Epstein-Barr virus infection. Both kinases represent interesting targets for inhibition: in the case of BTK, as an immunosuppressant, whereas there is evidence that the inhibition of inducible T-cell kinase (ITK) could influence the infectivity of HIV and also have anti-inflammatory activity. Since 2006, several patients carrying a fusion protein, originating from a translocation joining genes encoding the kinases ITK and spleen tyrosine kinase (SYK), have been shown to develop T-cell lymphoma. We review these disease processes and also describe the role of the N-terminal pleckstrin homology-Tec homology (PH-TH) domain doublet of BTK and ITK in the downstream intracellular signaling of such fusion proteins.
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Brunei Darussalam Elsewhere Brunei Int Med J. 2011; 7 (4): 240-243
This section of the journal serves to highlight the works and researches done by local
doctors or doctors either in Brunei Darussalam or in collaborations with other centers
that have been published in regional or international journals. This also includes works
published as part of collaboration with centers outside of Brunei Darussalam. These
works include review articles, original articles and case reports published between 16th
June to 15th August 2011. (Some publications have been published or indexed at a later
date than publication).
TEC-family kinases in health and
disease: Loss-of-function of BTK and
ITK and the gain-of-function fusions
ITK-SYK and BTK-SYK.
Hussain A, Yu L, Faryal R, Mohammad DK, Mo-
hamed AJ, Edvard Smith CI.
FEBS J. 2011 Apr 23. doi: 10.1111/j.1742-
4658.2011.08134.x.
The TEC-family constitutes an ancient and the sec-
ond largest family of cytoplasmic tyrosine kinases.
In 1993 loss-of-function mutations in the BTK gene
were reported as the cause of X-linked agammag-
lobulinemia (XLA). Out of all the existing 90 tyro-
sine kinases in humans, BTK is the kinase where
most mutations have been identified. These experi-
ments of nature collectively provide a form of mu-
tation scanning with direct implications for those
several hundred endogenous signaling proteins
carrying domains also found in BTK. In 2009 an
inactivating mutation in the ITK gene was shown to
cause susceptibility to lethal Epstein-Barr virus in-
fection (EBV). Both kinases represent interesting
targets for inhibition; in the case of BTK as an im-
munosuppressant, while there is evidence that inhi-
bition of ITK could influence the infectivity of HIV
and also have anti-inflammatory activity. Since
2006 several patients carrying a fusion protein,
originating from a translocation joining genes en-
coding the kinases ITK and SYK, were found to
develop T-cell lymphoma. We review these disease
processes and also describe the role of the N-
terminal PH-TH domain doublet of BTK and ITK in
the downstream intracellular signaling of such fu-
sion proteins.
Correspondence: Benjamin MA. Department of Obstetrics
and Gynecology, RIPAS Hospital, Bandar Seri Begawan,
Brunei. mridulaben@yahoo.com.
A r t i c l e i s a v ai l a bl e f r ee f r o m h t tp : / /
www.jmedicalcasereports.com/content/4/1/136 (Journal
website).
Basilar artery stenosis.
Bickle IC, Warren DJ, Genever A. Abdominal Imag-
ing. Case 8492. 10.1594/EURORAD/CASE.8492
This 35-year-old lady attended A & E complaining
of headache and brief loss of consciousne ss. After
an unremarkable clinical assessment she was dis-
charged home. Three hou rs later she returned with
similar symptoms and whilst awaiting review her
GSC dropped to 7/15. Intubation was required.
Prompt CT imaging of the head was performed.
Correspondence: Ian Bickle, Department of Radiology,
and Department of Medicine, RIPAS Hospital, Brunei Da-
russalam. Article available from EURORAD website at
http://www.eurorad.org/case.php?id=8492
Exophytic gastric adenocarcinoma.
Bickle I, Chong VH, Alludin BPM.Abdominal Imag-
ing. Case 9300. 10.1594/EURORAD/CASE.9300
This 79-year-old lady presented with a four week
history of upper abdominal pain, anorexia, vomiting
and mild weight loss. She denied any previous his-
tory of abdominal problems or melena. Her only
relevant past medical history was of hypertension
and dyslipidemia. Examination revealed a non-
tender epigastric mass.
Correspondence: Ian Bickle, Department of Radiology,
and Department of Medicine, RIPAS Hospital, Brunei Da-
russalam. Article available from EURORAD website at
http://www.eurorad.org/case.php?id=9300
Analysis of APC allelic imbalance/
loss of heterozygosity and APC
protein expression in cutaneous
squamous cell carcinomas.
Gray SE, Kay EW, Leader M, Mabruk M.
Brunei Int Med J. 2011; 7 (4): 241
Cancer Genomics Proteomics. 2011 May-Jun;8
(3):149-55.
BACKGROUND: The adenomatous polyposis coli
(APC) gene is a tumor suppressor gene which is
mutated in the hereditary disease, familial adeno-
matous polyposis (FAP). Somatic mutations of the
APC gene have also been identified in the majority
of sporadic colorectal carcinomas, and mutation of
the APC gene appears to be an early step in the
initiation of colon cancer. Loss of heterozygosity
(LOH) of APC has been described in a variety of
other cancer types, including renal cell carcinoma,
gastric cancer, non-small cell lung cancer, endo-
metrial cancer and oral squamous cell carcinomas
(SCC). Aim: To determine the role played by APC
gene in the genesis of cutaneous SCC. MATERIALS
AND METHODS: Allelic imbalance/loss of het-
erozygosity (AI/LOH) was examined in twenty-two
histologically confirmed cutaneous squamous cell
carcinomas (SCC) using microsatellite markers,
proximal to the APC gene. Immunohistochemical
analysis of APC protein expression was also exam-
ined in the cutaneous SCC. RESULTS: AI/LOH was
detected in 60% of the SCC samples using D5S346
marker (proximal to the APC gene). Ninty-five per-
cent of the SCC samples showed positive reduced
APC expression, however the localization of the APC
protein was abnormal. CONCLUSION: The abnor-
mal expression of APC suggests that APC gene may
play a role in cutaneous SCC development.
Correspondence: Professor M Mabruk, PAPRSB Institute
of Health Sciences, University of Brunei Darussalam Jalan
Tungku Link, Gadong BE1410 Bandar Seri Begawan,
Brunei Darussalam. Email to mabruk@ubd.edu.bn/
mmabruk03@yahoo.co.uk.
Comparison of RIPASA and Alvarado
scores for the diagnosis of acute
appendicitis
Chong CF, Thien A, Mackie AJA, Tin AS, Tripathi S,
Ahmad MA, Tan LT, Ang SH, Telisinghe PU.
Singapore Med J 2011:52(5):340-5.
Introduction: The accuracy of the Alvarado score
in diagnosing acute appendicitis in an Asian popula-
tion has been disappointingly low. We prospectively
compared the RIPASA score with the Alvarado
score for the diagnosis of acute appendicitis. Meth-
ods: 200 consecutive patients who presented to
the Accident and Emergency Department with right
iliac fossa pain were recruited in the study. Both
the RIPASA and Alvarado scores were derived, but
decisions for appendicectomy were based on clinical
judgement. Receiver operating curve (ROC), sen si-
tivity, specificity, positive predictive value (PPV)
and negative predictive value (NPV) for both scor-
ing systems were calculated. Results: Only 192
out of the 200 patients who satisfied the inclusion
and exclusion criteria were included in the analysis.
At the optimal cut-off threshold score of 7.5 derived
from the ROC, the sensitivity, specificity, PPV, NPV
and diagnostic accuracy of the RIPASA score were
98.0 percent, 81.3 percent, 85.3 percent, 97.4 per-
cent and 91.8 percent, respectively. At the cut-off
threshold score of 7.0 for the Alvarado score, the
sensitivity, specificity, PPV, NPV and diagnostic
accuracy were 68.3 percent, 87.9 percent, 86.3
percent, 71.4 percent and 86.5 percent, respec-
tively. The RIPASA score correctly classified 98 per-
cent of all patients confirmed with histological acute
appendicitis to the high-probability group (RIPASA
score greater than 7.5) compared with 68.3 per-
cent with the Alvarado score (Alvarado score
greater than 7.0; p-value less than 0.0001). Con-
clusion: The RIPASA score at a cut-off threshold
total score of 7.5 is a better diagnostic scoring sys-
tem than the Alvarado score for the diagnosis of
acute appendicitis in our local setting.
Correspondence: Chong CF. Department of General Sur-
gery, Raja Isteri Pengiran Anak Saleha Hospital, Bandar
Seri Begawan, BA 1710, Brunei Darussal am.
Email: chong_chee_fui@hotmail.com. Article available free
from http://smj.sma.org.sg/5205/5205a2.pdf (Journal
website)
Melioidosis of the extremities in
Brunei Darussalam
Pande KC, Hj Abdul Kadir KA. Singapore Med J
2011:52(5):346-50.
Introduction: Melioidosis caused by Burkholderia
pseudomallei is an infectious disease endemic to
Southeast Asia and northern Australia. It has a
broad spectrum of clinical manifestations and high
mortality, and can mimic other infectious diseases.
The aim of this study was to review cases of melioi-
dosis of the extremities in Brunei Darussalam.
Methods: Culture-positive cases for Burkholderia
pseudomallei in Raja Isteri Pengiran Anak Saleha
Hospital were identified from records in the Microbi-
ology Department. The case notes were reviewed
to identify patients who were treated for problems
affecting the extremities. 14 (13 males and one
female) out of 48 patients were identified. Results:
The median age of the patients was 45 (range 14–
55) years. Septicaemia was the most common pre-
senting feature in 11 patients. Multisystem involve-
ment was noted in eight patients, diabetes mellitus
in nine patients and other risk factors in two pa-
tients. Blood culture was positive in ten patients
and pus culture in 11 patients. The presentations
noted were cellulitis of the limbs, abscess, osteo-
myelitis (three patients each) and septic arthritis
(five patients). Orthopaedic intervention (joint
washout/incision and drainage/curettage) was re-
quired in 11 patients. The median hospital stay was
27.5 (range 13–63) days; two patients required
admission to intensive care. No mortality was re-
ported. Conclusion: Melioidosis of the extremities
is not uncommon in Brunei Darussalam. It is asso-
ciated with significant morbidity, and a large num-
ber of patients require surgical intervention. Thus,
a high index of suspicion is required for early diag-
nosis and institution of appropriate antibiotic ther-
apy.
Correspondence: Pande KC. Department of Orthropae-
dics, Raja Isteri Pengiran Anak Saleha Hospital, Bandar
Seri Begawan, BA 1710, Brunei Darussal am.
E mail: ketanpande@yahoo.com.
Article available free from http://
smj.sma.org.sg/5205/5205a3.pdf (Journal website)
Physician home visit by palliative
medical fellow.
Ang SK, Legrand SB, Walsh D, Davis MP, Lagman
RL. Am J Hosp Palliat Care. 2011 Jun 10. [Epub
ahead of print]
BACKGROUND: Physician home visits (HVs) are an
important model of care for the terminally ill. Hos-
pice and palliative medicine (HPM) fellows make a
minimum of 25 HVs. OBJECTIVE: To describe HPM
fellow hospice HVs in an academic palliative medi-
cine practice. METHODS: Retrospective chart re-
view of HVs conducted by 1 HPM fellow. RESULTS:
Twenty-five HVs were made to 21 hospice patients.
Nineteen had advanced cancer. Indications for vis-
its were symptom management (22) and education
(21). On average 2.8 symptoms (± SD 1) were
addressed on each visit, usually pain. Medications
were reviewed at every visit. CONCLUSIONS: HVs
are an important part for patient care and fellow
education, which provided an opportunity for medi-
cation revision and sympto m education.
Correspondence: Ang SK. Department of I nternal Medi-
cine, RIPAS Hospital, Bandar Seri Begawan, Brunei. E mail:
Sikim2000@gmail.com
Performance and cross-cultural
comparison of the short-form
version of the CPQ11-14 in
New Zealand, Brunei and Brazil.
Foster Page LA, Thomson WM, Mohamed AR, Trae-
bert J. Health Qual Life Outcomes. 2011 Jun 7;9
(1):40. [Epub ahead of print]
BACKGROUND: The Child Perception Question-
naire (CPQ11- 14) is a self-report instrument devel-
oped to measure oral-health-related quality of life
(OHRQoL) in 11-14-year-olds. Earlier reports con-
firm that the 16-item short-form version performs
adequately, but there is a need to determine the
measure's validity and properties in larger and
more diverse samples and settings. Aim: The ob-
jective of this study was to examine the perform-
ance of the 16-item short-form impact version of
the CPQ11-14 in different communitie s and cultures
with diverse caries experience. METHOD: Cross-
sectional epidemiological surveys of child oral
health were conducted in two regions of New Zea-
land, one region in Brunei, and one in Brazil. Chil-
dren were examined for dental caries (following
WHO guidelines), and OHRQoL was measured using
the 16-item short-form item-impact version of the
CPQ11-14, along with two global questions on
OHRQoL. Children in the 20% with the greatest
caries experience (DMF score) were categorised as
the highest caries quintile. Construct validity was
evaluated by comparing the mean scale scores
across the categories of caries experience; correla-
tional construct validity was assessed by comparing
mean scores and children's global ratings of oral
health and well-being. RESULTS: There were sub-
stantial variations in caries experience among the
different communities (from 1.8 in Otago to 4.9 in
Northland) and in mean CPQ11-14 scores (from
11.5 in Northland to 16.8 in Brunei). In all samples,
those in the most severe caries experience quintile
had higher mean CPQ11-14 scores than those who
were caries-free (P<0.05). There were also greater
CPQ scores in those with worse self-rated oral
health, with the Otago sample presenting the most
marked gradient across the response categories for
self-rated oral health, from 'Excellent' to 'Fair/
Poor' (9.6 to 19.7 respectively). CONCLUSION:
The findings suggest that the 16-item short-form
item impact version of the CPQ11-14 performs well
across diverse cultures and levels of caries experi-
ence. Reasons for the differences in mean CPQ
scores among the communities are unclear and
may reflect subtle socio-cultural differences in sub-
jective oral health among these populations, but
elucidating these requires further exploration of the
face and content validity of the measure in different
populations. Key Words: Adolescents, caries experi-
ence, quality of life, validity, short-form CPQ11-14.
Brunei Int Med J. 2011; 7 (4): 242
Brunei Int Med J. 2011; 7 (4): 243
Complete Dislocation of the Lens of
the Eye - Always review the com-
plete study.
Bickle I. Philipp J Otolaryngol Head Neck Surg
2011; 26(1):49-50. ICID: 945452
This 37 year-old male patient underwent high reso-
lution CT imaging of the face including the parana-
sal sinuses following trauma.
Correspondence: Ian Bickle, Department of Radiology,
and Department of Medicine, RIPAS Hospital, Brunei Da-
russalam. Article available from http://pso-hns.org/
psojournals/pjohns/2011a/07-from-the-viewbox.pdf
Alveolar rhabdomyosarcoma
Bickle IC. Paediatric Radiology. Case 9384.
10.1594/EURORAD/CASE.9384
This 8-year-old girl presented to paediatric outpa-
tient clinic after her mother noticed a mass within
the central abdomen. There were no further symp-
toms. Clinical examination confirmed the presence
of a painless firm mass extending from the pelvis to
above the umblicus. Alpha fetoprotein and HCG
were normal.
Correspondence: Ian Bickle, Department of Radiology,
and Department of Medicine, RIPAS Hospital, Brunei Da-
russalam. Article available from EURORAD website at
http://www.eurorad.org/case.php?id=9384
BOOK CHAPTERS
Operative Oral and Maxillofacial
Surgery. Ed. Langdon J, Patel M, Ord
R and Brennan P. Arnold Fodder
publishing. 2010.
PART ELEVEN: FACIAL AESTHETIC SURGERY
11.1 Nonsurgical techniques: botox, fillers.
N Ravindranathan
11.2 Hair transplantation
N Ravindranathan and E Antonio Mangubat
11.6 Rhinoplasty and septoplasty: Closed and open
techniques and the Oriental nose.
Luc Cesteleyn, N Ravindranathan and Corazon
Collantes Jose

Supplementary resource (1)

FEBS
Data
April 2014
Alamdar Hussain · Liang Yu · Rani Faryal · Dara K. Mohammad · Edvard C I Smith
... Mammalian Tec (tyrosine kinase expressed in hepatocellular carcinoma) family of tyrosine kinases (TFKs) are cytoplasmic (or non-receptor) kinases that evolved million years ago (Bhullar et al., 2018;Tan et al., 2019;Yamaoka et al., 2018). All mammalian TEC family kinases (TFKs) are composed of five different kinases: Bruton's tyrosine kinase (BTK), inducible T-cell kinase (ITK), TEC, BMX [also known as epithelial and endothelial tyrosine kinase (ETK)] and TXK [also known as resting lymphocyte kinase (RLK)] (Hussain et al., 2011). ...
... These domains are crucial inhibitory targets for ITK activation. Nevertheless, it is possible that PH, SH3, and SH2 domains modulate ITK and signaling pathways outside of the kinase domain (Hussain et al., 2011). ...
Identification of IL-2 inducible tyrosine kinase inhibitors by quantum mechanics and ligand based virtual screening approaches
Article
Interleukin-2-inducible T-cell kinase (ITK) is a crucial intracellular signaling mediator in normal and malignant T-cells and natural killer cells. Selective inhibition of ITK might be useful for treating a variety of disorders including; autoimmune, inflammatory, and neoplastic disorders. Over the past two decades, the clinical management of ITK inhibitors has progressed dramatically. So far, specific inhibitor with no off-target effects against ITK is available. Herein, we aim to discover potential virtual hits to fasten the process of drug design and development against ITK. In this regard, the key chemical characteristics of ITK inhibitors were identified using ligand-based pharmacophore modeling. The validated pharmacophore comprises one hydrogen bond donor and three hydrogen bond acceptors and was utilized as a 3D query in virtual screening using ZINC, Covalent, and in-house databases. A total of 12 hit compounds were chosen on the basis of their critical interactions with the significant amino acids of ITK. The orbital energies such as HOMO and LUMO of the hit compounds were calculated to evaluate the inhibitor's potencies. Further, molecular dynamics simulation demonstrated the stability of ITK upon binding of selected virtual hits. Binding energy using the MMGBSA method showed the potential binding affinity of all the hits with ITK. The research identifies key chemical characteristics with geometric restrictions that lead to ITK inhibition.Communicated by Ramaswamy H. Sarma.
View
... Both subtypes of protein kinases are important stimulators of a wide range of essential physiological processes such as cell cycle regulation, protein synthesis, angiogenesis, and homeostasis [5]. Owing to their great involvement in cell growth and proliferation [5], Hussain et al. and others reported that the pathological deregulation of these protein kinases is implicated in the growth of oncogenes and tumors [5][6][7][8][9][10]. Hence, the identification and development of specific therapies targeted at protein kinases such as RTKS, PI3K, and mTOR can be perceived as potential cancer therapies resulting in an improvement of survival rate and quality of life of cancer patients. ...
... Tyrosine kinases are the enzymes that can catalyze a phosphate group from ATP to serine or tyrosine residues [5]. Several years ago, it was investigated that phosphorylation of protein by tyrosine kinases is an important mechanism in modulating signal transduction cascades [7,8,52], and controlling numerous biological processes like cell growth, proliferation, differentiation, and metabolism [52]. Tyrosine kinases can be classified into RTKs and non-receptor tyrosine kinases. ...
Role of receptor tyrosine kinases mediated signal transduction pathways in tumor growth and angiogenesis—New insight and futuristic vision
Article
  • Mar 2021
  • INT J BIOL MACROMOL
Significant progress has been made in the past two decades towards the understanding of the basic mechanisms underlying cancer growth and angiogenesis. In this context, receptor tyrosine kinases (RTKs) play a pivotal role in cell proliferation, differentiation, growth, motility, invasion, and angiogenesis, all of which contribute to tumor growth and progression. Mutations in RTKs lead to abnormal signal transductions in several pathways such as Ras-Raf, MEK-MAPK, PI3K-AKT and mTOR pathways, which affects protein translation and a wide range of biological functions including cell proliferation, survival, migration and vascular permeability. Increasing evidence demonstrates that multiple kinases are involved in angiogenesis including RTKs such as vascular endothelial growth factor, platelet derived growth factor, epidermal growth factor, insulin-like growth factor-1, macrophage colony-stimulating factor, nerve growth factor, fibroblast growth factor, Hepatocyte Growth factor, Tie 1 & 2, Tek, Flt-3, Flt-4 and Eph receptors. Overactivation of RTKs and its downstream regulation is implicated in tumor initiation and angiogenesis, which represents one of the hallmarks of cancer. This review discusses the role of RTKs, PI3K, and mTOR, their involvement and their implication in pro-oncogenic cellular processes and angiogenesis with effective approaches and newly approved drugs to inhibit their excessive action.
View
... Shared TFs and COFs were identified between liver and muscle (n = 13), muscle and rumen (n = 23), rumen and liver (n = 21) and liver, muscle, and rumen (n = 1, cofactor BTK). BTK is a key regulator of the B-cell receptor (BCR) signaling pathway 51 . This pathway plays a crucial role in regulating B-cell survival, proliferation, and maturation, and also regulates several downstream signaling pathways, including the MAPK and AKT pathways 52 . ...
Transcriptional response to an alternative diet on liver, muscle, and rumen of beef cattle
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Full-text available
  • Jun 2024
Feed cost represents a major economic determinant within cattle production, amounting to an estimated 75% of the total variable costs. Consequently, comprehensive approaches such as optimizing feed utilization through alternative feed sources, alongside the selection of feed-efficient animals, are of great significance. Here, we investigate the effect of two diets, traditional corn-grain fed and alternative by-product based, on 14 phenotypes related to feed, methane emission and production efficiency and on multi-tissue transcriptomics data from liver, muscle, and rumen wall, derived from 52 Nellore bulls, 26 on each diet. To this end, diets were contrasted at the level of phenotype, gene expression, and gene-phenotype network connectivity. As regards the phenotypic level, at a P value < 0.05, significant differences were found in favour of the alternative diet for average daily weight gain at finishing, dry matter intake at finishing, methane emission, carcass yield and subcutaneous fat thickness at the rib-eye muscle area. In terms of the transcriptional level of the 14,776 genes expressed across the examined tissues, we found 487, 484, and 499 genes differentially expressed due to diet in liver, muscle, and rumen, respectively (P value < 0.01). To explore differentially connected phenotypes across both diet-based networks, we focused on the phenotypes with the largest change in average number of connections within diets and tissues, namely methane emission and carcass yield, highlighting, in particular, gene expression changes involving SREBF2, and revealing the largest differential connectivity in rumen and muscle, respectively. Similarly, from examination of differentially connected genes across diets, the top-ranked most differentially connected regulators within each tissue were MEOX1, PTTG1, and BASP1 in liver, muscle, and rumen, respectively. Changes in gene co-expression patterns suggest activation or suppression of specific biological processes and pathways in response to dietary interventions, consequently impacting the phenotype. The identification of genes that respond differently to diets and their associated phenotypic effects serves as a crucial stepping stone for further investigations, aiming to build upon our discoveries. Ultimately, such advancements hold the promise of improving animal welfare, productivity, and sustainability in livestock farming.
View
... BTK located in the cytoplasm, is a non-receptor tyrosine kinase, belonging to the TEC family of kinases [26][27][28]. Its gene encodes a protein with 659 amino acids, including a single kinase domain and multiple protein interaction domains [29]. ...
Overexpression of Bruton Tyrosine Kinase Inhibits the Proliferation, Migration, and Invasion of Non-Small Cell Lung Cancer Cells
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Full-text available
Lung cancer is one of the most lethal malignant tumors in the world. Non-small cell lung cancer (NSCLC) is the most common pathological subtype. However, the molecular mechanism of NSCLC progress is still unclear. We extracted the expression data of the Bruton’s tyrosine kinase (BTK) gene in NSCLC tissues from the TCGA database. The results of paired t-test showed that the BTK gene was significantly underexpressed in NSCLC tissues. To further verify the above results, we detected the expression of the BTK gene in NSCLC cell lines A549, H1299, and H1650 at the RNA and protein levels by real-time fluorescent quantitative polymerase chain reaction and Western Blot analysis, respectively. The results showed that BTK was low expressed in NSCLC tissues and cells. More importantly, the expression of the BTK gene is also significantly related to the patient’s age, gender, tumor range (T), lymph node invasion (N), tumor stage, and prognosis, and its expression level gradually decreases with the progress of the disease. It is speculated that BTK may be an independent prognostic factor of NSCLC. Our experimental results are consistent with the above clinical correlation analysis results. Overexpression of BTK can significantly inhibit the proliferation, migration, and invasion of NSCLC cells and can block the G0/G1 tumor cell cycle, indicating that overexpression of BTK can inhibit the growth, migration, and invasion of NSCLC cells.
View
... 14 In addition, the ITK-SYK fusion protein has been shown to promote T-cell lymphoma and inflammation. 15 ...
Immunomodulatory role of spleen tyrosine kinase in chronic inflammatory and autoimmune diseases
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  • Jul 2023
Background: The high prevalence of chronic inflammatory diseases or autoimmune reactions is a major source of concern and affects the quality of life of patients. Chronic inflammatory or autoimmune diseases are associated with many diseases in humans, including asthma, rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease and cancer. Splenic tyrosine kinase (SYK) is a non-receptor tyrosine kinase that plays an important role in immune receptor signalling in immune and inflammatory responses. Methods: This is a review article in which we searched for keywords "splenic tyrosine kinase", "inflammation" and "autoimmune diseases" in published literature such as Pubmed and Web of Science to collect relevant information and then conducted a study focusing on the latest findings on the involvement of SYK in chronic inflammatory or autoimmune diseases. Results: This paper reviews the regulation of Fcγ, NF-κB, B cell and T cell-related signalling pathways by SYK, which contributes to disease progression in chronic inflammatory and autoimmune diseases such as airway fibrosis, inflammatory skin disease and inflammatory bowel disease. Conclusion: This paper shows that SYK plays an important role in chronic inflammatory and autoimmune diseases. syk targets hematological, autoimmune and other inflammatory diseases and therefore, inhibition of SYK expression or blocking its related pathways may provide new ideas for clinical prevention and treatment of inflammatory or autoimmune diseases.
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... TEC family kinase has five different members, namely; Bruton's tyrosine kinase (Btk), inducible T-cell kinase (Itk), TEC (tyrosine kinase expressed in hepatocellular carcinoma), bone marrow-expressed kinase (Bmx), epithelial and endothelial tyrosine kinase (Etk), and resting lymphocyte kinase (Rlk). This family distinguishes itself from other NRTKs based on two different properties; a proline-rich region and a pleckstrin homology domain [42,43]. This family is specifically expressed in the liver and kidney and is involved in the regulation of multiple cellular processes. ...
A Concise Review on Tyrosine Kinase Targeted Cancer Therapy
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The tyrosine kinase (TK) family is considered one of the important family members of the kinase family due to its important role in various cellular processes like cell growth, cell differentiation, apoptosis, etc. Mutation, overexpression, and dysfunction of tyrosine kinase receptors lead to the development of malignancy; thus, they are considered as one of the important targets for the development of anti-cancer molecules. The tyrosine kinase family is majorly divided into two classes; receptor and non-receptor tyrosine kinase. Both of the classes have an important role in the development of tumour cells. Currently, there are more than 40 FDA-approved tyrosine kinase inhibitors, which are used in the treatment of various types of cancers. Tyrosine kinase inhibitors mainly block the phosphorylation of tyrosine residue of the corresponding kinase substrate and so activation of downstream signalling pathways can be inhibited. The promising results of tyrosine kinase inhibitors in solid tumours provide a revolution in oncology research. In this article, we had summarized the role of some important members of the tyrosine kinase family in the development and progression of tumour cells and the significance of tyrosine kinase inhibitors in the treatment of various types of cancer.
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... Bruton's tyrosine kinase (BTK) is a non-receptor intracellular kinase that belongs to the Tec (tyrosine kinase expressed in hepatocellular carcinoma) family [1,2]. Generally, BTK is located in a cytoplasmic position, yet it can be briefly recruited to the cell membrane via interaction with phosphatidylinositol-3,4,5-triphosphate (PIP 3 ), a phospholipid effector activated by phosphatidylinositol-3 kinase (PI3K) [3]. ...
Bruton’s tyrosine kinase: an emerging targeted therapy in myeloid cells within the tumor microenvironment
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  • Sep 2021
  • CANCER IMMUNOL IMMUN
Bruton’s tyrosine kinase (BTK) is a non-receptor kinase belonging to the Tec family of kinases. The role of BTK in B cell receptor signaling is well defined and is known to play a key role in the proliferation and survival of malignant B cells. Moreover, BTK has been found to be expressed in cells of the myeloid lineage. BTK has been shown to contribute to a variety of cellular pathways in myeloid cells including signaling in the NLRP3 inflammasome, receptor activation of nuclear factor-κβ and inflammation, chemokine receptor activation affecting migration, and phagocytosis. Myeloid cells are crucial components of the tumor microenvironment and suppressive myeloid cells contribute to cancer progression, highlighting a potential role for BTK inhibition in the treatment of malignancy. The increased interest in BTK inhibition in cancer has resulted in many preclinical studies that are testing the efficacy of using single-agent BTK inhibitors. Moreover, the ability of tumor cells to develop resistance to single-agent checkpoint inhibitors has resulted in clinical studies utilizing BTK inhibitors in combination with these agents to improve clinical responses. Furthermore, BTK regulates the immune response in microbial and viral infections through B cells and myeloid cells such as monocytes and macrophages. In this review, we describe the role that BTK plays in supporting suppressive myeloid cells, including myeloid-derived suppressor cells (MDSC) and tumor-associated macrophages (TAM), while also discussing the anticancer effects of BTK inhibition and briefly describe the role of BTK signaling and BTK inhibition in microbial and viral infections.
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... Bruton tyrosine kinase (BTK) is an important regulator of B cell receptor (BCR) signaling pathway. 3,4 Chronic and sustained activation of the BCR signaling pathway is related to the pathogenesis of many subtypes of B cell malignancies. 5 The first-generation BTK inhibitor ibrutinib has presented with remarkable efficacy in several hematological malignancies, and it has been currently approved for the treatment of mantle cell lymphoma (MCL), chronic lymphocytic leukemia (CLL), and Waldenstrom macroglobulinemia (WM). ...
Addition of BTK inhibitor Orelabrutinib to Rituximab improved anti-tumor effects in B cell lymphoma
Article
Full-text available
  • Apr 2021
Bruton tyrosine kinase (BTK) inhibitor ibrutinib has been validated as an effective drug to treat B-cell malignancies. Combined therapies comprising ibrutinib and anti-CD20 antibodies like rituximab were designed as a backbone in many clinical trials. However, the off-target inhibition of ibrutinib on IL2-inducible T-cell kinase (ITK) may reduce rituximab’s ADCC efficacy. Orelabrutinib (Orel), a novel BTK inhibitor, was designed with high selectivity to BTK. In our study, we demonstrated in preclinical models that Orelabrutinib in combination with rituximab could preserve NK-cell-mediated antibody-dependent cellular cytotoxicity (ADCC) induced by rituximab and enhanced the apoptosis of tumor cells in vitro. The addition of Orelabrutinib to rituximab had produced promising combined anti-tumor effects in B cell lymphomas in vivo. Collectively, combination therapy of Orelabrutinib with rituximab would benefit patients with B cell lymphoma, especially those with relapsed or refractory disease.
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Pleckstrin Homology [PH] domain, structure, mechanism, and contribution to human disease
Article
  • Jul 2023
The pleckstrin homology [PH] domain is a structural fold found in more than 250 proteins making it the 11th most common domain in the human proteome. 25% of family members have more than one PH domain and some PH domains are split by one, or several other, protein domains although still folding to give functioning PH domains. We review mechanisms of PH domain activity, the role PH domain mutation plays in human disease including cancer, hyperproliferation, neurodegeneration, inflammation, and infection, and discuss pharmacotherapeutic approaches to regulate PH domain activity for the treatment of human disease. Almost half PH domain family members bind phosphatidylinositols [PIs] that attach the host protein to cell membranes where they interact with other membrane proteins to give signaling complexes or cytoskeleton scaffold platforms. A PH domain in its native state may fold over other protein domains thereby preventing substrate access to a catalytic site or binding with other proteins. The resulting autoinhibition can be released by PI binding to the PH domain, or by protein phosphorylation thus providing fine tuning of the cellular control of PH domain protein activity. For many years the PH domain was thought to be undruggable until high-resolution structures of human PH domains allowed structure-based design of novel inhibitors that selectively bind the PH domain. Allosteric inhibitors of the Akt1 PH domain have already been tested in cancer patients and for proteus syndrome, with several other PH domain inhibitors in preclinical development for treatment of other human diseases.
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Trends of Receptor Tyrosine Kinase Researches Based on Bibliometric Analysis
Article
  • May 2022
Malignant tumor is one of the diseases threatening human life and health. Traditional antitumor therapy has some limitations in clinical application, so the development of targeted antitumor drugs has become one of the important research directions of cancer medicine. Since the first tyrosine kinase inhibitor was approved in 2001, this research field has attracted global attention. In this survey, the Web of Science database was adopted to make a bibliometric analysis of the global scientific production of receptor tyrosine kinases in recent 20 years. A total of 14378 documents related to the subject were retrieved and analyzed according to six main aspects: area, journal, country, institution, authors, and keywords. The results show that the United States is currently in a leading position in this field and has established the largest cooperation network with other countries. Harvard University has made the greatest contribution to the field of receptor tyrosine kinases, including the number of publications, the average number of citations per paper, and the h-index. Besides, PLOS One ranked first among the top 15 academic journals in the number of publications related to receptor tyrosine kinases during the survey period. Our research comprehensively evaluates the research status and cooperation network of receptor tyrosine kinases, hoping help researchers to guide their projects or find potential collaborators.
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BTKbase, Mutation Database for X-Linked Agammaglobulinemia (XLA)
Article
Full-text available
  • Jan 1998
  • NUCLEIC ACIDS RES
X-linked agammaglobulinemia (XLA) is an immunodeficiency caused by mutations in the gene coding for Bruton's agammaglobulinemia tyrosine kinase (BTK). A database (BTKbase) of BTK mutations has been compiled and the recent update lists 463 mutation entries from 406 unrelated families showing 303 unique molecular events. In addition to mutations, the database also lists variants or polymorphisms. Each patient is given a unique patient identity number (PIN). Information is included regarding the phenotype including symptoms. Mutations in all the five domains of BTK have been noticed to cause the disease, the most common event being missense mutations. The mutations appear almost uniformly throughout the molecule and frequently affect CpG sites that code for arginine residues. The putative structural implications of all the missense mutations are given in the database. The improved version of the registry having a number of new features is available at http://www.helsinki.fi/science/signal/btkbase.html
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Identification, cloning, and characterization of a novel human T-cell- specific tyrosine kinase located at the hematopoietin complex on chromosome 5q
Article
  • Sep 1993
Signal transduction through the T-cell receptor and cytokine receptors on the surface of T lymphocytes occurs largely via tyrosine phosphorylation of intracellular substrates. Because neither the T-cell receptor nor cytokine receptors contain intrinsic kinase domains, signal transduction is thought to occur via association of these receptors with intracellular protein tyrosine kinases. Although several members of the SRC and SYK families of tyrosine kinases have been implicated in signal transduction in lymphocytes, it seems likely that additional tyrosine kinases involved in signal transduction remain to be identified. To identify unique T-cell tyrosine kinases, we used polymerase chain reaction-based cloning with degenerate oligonucleotides directed at highly conserved motifs of tyrosine kinase domains. We have cloned the complete cDNA for a unique human tyrosine kinase that is expressed mainly in T lymphocytes (EMT) and natural killer (NK) cells. The cDNA of EMT predicts an open reading frame of 1866 bp encoding a protein with a predicted size of 72 Kd, which is in keeping with its size on Western blotting. A single 6.2-kb EMT mRNA and 72-Kd protein were detected in T lymphocytes and NK-like cell lines, but were not detected in other cell lineages. EMT contains both SH2 and SH3 domains, as do many other intracellular kinases. EMT does not contain the N-terminal myristylation site or the negative regulatory tyrosine phosphorylation site in its carboxyterminus that are found in the SRC family of tyrosine kinases. EMT is related to the B-cell progenitor kinase (BPK), which has recently been implicated in X-linked hypogammaglobulinemia, to the TECI mammalian kinase, which has been implicated in liver neoplasia, to the more widely expressed TECII mammalian kinase, and to the Drosophila melanogaster Dsrc28 kinase. Sequence comparison suggests that EMT is likely the human homologue of a recently identified murine interleukin-2 (IL-2)-inducible T cell kinase (ITK). However, unlike ITK, EMT message and protein levels do not vary markedly on stimulation of human IL-2-responsive T cells with IL-2. Taken together, it seems that EMT is a member of a new family of intracellular kinases that includes BPK, TECI, and TECII. EMT was localized to chromosome 5q31–32, a region that contains the genes for several growth factors and receptors as well as early activation genes, particularly those involved in the hematopoietic system. Furthermore, the 5q31–32 region is implicated in the genesis of the 5q- syndrome associated with myelodysplasia and development of leukemia.(ABSTRACT TRUNCATED AT 400 WORDS)
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A Key Role for Itk in Both IFNγ and IL-4 Production by NKT Cells1
Article
  • Jul 2007
NKT cells rapidly secrete cytokines upon TCR stimulation and thus may modulate the acquired immune response. Recent studies suggest that signaling for development and effector function in NKT cells may differ from conventional T cells. The tyrosine kinase Itk is activated downstream of the TCR, and its absence in CD4+ T cells results in impaired Th2, but not Th1 responses. In this study, we investigated NKT cell function in the absence of Itk as impaired type 2 responses in vivo could be manifest through IL-4 defects in a number of cell types. We show that Itk-deficient NKT cells up-regulate IL-4 mRNA in the thymus and express constitutive IL-4 and IFN-γ transcripts in peripheral organs. Thus, Itk is not required for the developmental activation of cytokine loci in NKT cells. Nevertheless, Itk-deficient NKT cells are severely impaired in IL-4 protein production. Strikingly, unlike conventional CD4+ T cells, Itk-deficient NKT cells also have profound defects in IFN-γ production. Furthermore, both IL-4 and IFN-γ production were markedly impaired following in vivo challenge with α-galactosyl ceramide. Function can be restored in Itk-deficient NKT cells by provision of calcium signals using ionomycin. These results suggest that NKT cells are highly dependent on Itk for IL-4- and IFN-γ-mediated effector function. Thus, the pattern of cytokine genes that are affected by Itk deficiency appears to be cell lineage-specific, likely reflecting differences in activation threshold between immune effectors. The severe defect in NKT cell function may underlie a number of the Th1 and Th2 immune defects in Itk-deficient mice.
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BTKbase: The Mutation Database for X-Linked Agammaglobulinemia
Article
X-linked agammaglobulinemia (XLA) is a hereditary immunodeficiency caused by mutations in the gene encoding Bruton tyrosine kinase (BTK). XLA patients have a decreased number of mature B cells and a lack of all immunoglobulin isotypes, resulting in susceptibility to severe bacterial infections. XLA-causing mutations are collected in a mutation database (BTKbase), which is available at http://bioinf.uta.fi/BTKbase. For each patient the following information is given (when available): the identification of the entry, a plain English description of the mutation followed by a reference, formal characterization of the mutation, and the various parameters from the patient. BTKbase is implemented with the MUTbase program suite, which provides an easy, interactive, and quality controlled submission of information to mutation databases. BTKbase version 8 lists mutation entries of 1,111 patients from 973 unrelated families showing 602 unique molecular events. The localization of the mutations on the gene and protein for BTK can be analyzed by clicking sequences on the web pages. The distribution of the mutations in the five structural domains is approximately proportional to the length of the domains, except for the Tec homology (TH) domain. The most frequently affected sites are CpG dinucleotides. The majority of the missense mutations are structural—disturbing Bruton tyrosine kinase (Btk) folding or decreasing stability. Many of the mutations affect functionally significant, conserved residues. The structural consequences of the mutations in all the domains have been studied based on crystallographic and nuclear magnetic resonance (NMR) structures as well as computer-aided molecular modeling. Hum Mutat 27(12), 1209–1217, 2006. © 2006 Wiley-Liss, Inc.
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The gene involved in X-linked agammaglobulinemia is a member of the SRC family of protein-tyrosine kinases
Article
  • Apr 2012
  • J IMMUNOL
X-linked agammaglobulinaemia (XLA) is a human immunodeficiency caused by failure of pre-B cells in the bone marrow to develop into circulating mature B cells. A novel gene has been isolated which maps to the XLA locus, is expressed in B cells, and shows mutations in families with the disorder. The gene is a member of the src family of proto-oncogenes which encode protein-tyrosine kinases. This is, to our knowledge, the first evidence that mutations in a src-related gene are involved in human genetic disease.
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Deficient expression of a B cell cytoplasmic tyrosine kinase in human X-linked agammaglobulinemia
Article
  • Apr 2012
  • J IMMUNOL
We describe a novel cytoplasmic tyrosine kinase, termed BPK (B cell progenitor kinase), which is expressed in all stages of the B lineage and in myeloid cells. BPK has classic SH1, SH2, and SH3 domains, but lacks myristylation signals and a regulatory phosphorylation site corresponding to tyrosine 527 of c-src. BPK has a long, basic amino-terminal region upstream of the SH3 domain. BPK was evaluated as a candidate for human X-linked agammaglobulinemia (XLA), an inherited immunodeficiency characterized by a severe deficit of B and plasma cells and profound hypogammaglobulinemia. BPK mapped to within 100 kb of a probe defining the polymorphism most closely linked to XLA at DXS178. Reduction in or the absence of BPK mRNA, protein expression, and kinase activity was observed in XLA pre-B and B cell lines. BPK is likely the XLA gene and functions in pathways critical to 8 cell expansion.
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Subcutaneous immunoglobulin: Opportunities and outlook
Article
  • Dec 2009
  • CLIN EXP IMMUNOL
Immunoglobulin (Ig) administration via the subcutaneous (s.c.) route has become increasingly popular in recent years. The method does not require venous access, is associated with few systemic side effects and has been reported to improve patients' quality of life. One current limitation to its use is the large volumes which need to be administered. Due to the inability of tissue to accept such large volumes, frequent administration at multiple sites is necessary. Most studies conducted to date have investigated the use of subcutaneous immunoglobulin (SCIg) in patients treated previously with the intravenous (i.v.) formulation. New data now support the use of s.c. administration in previously untreated patients with primary immunodeficiencies. SCIg treatment may further be beneficial in the treatment of autoimmune neurological conditions, such as multi-focal motor neuropathy; however, controlled trials directly comparing the s.c. and i.v. routes are still to be performed for this indication. New developments may further improve and facilitate the s.c. administration route. For example, hyaluronidase-facilitated administration increases the bioavailability of SCIg, and may allow for the administration of larger volumes at a single site. Alternatively, more concentrated formulations may reduce the volume required for administration, and a rapid-push technique may allow for shorter administration times. As these developments translate into clinical practice, more physicians and patients may choose the s.c. administration route in the future.
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The Linker between SH2 and Kinase Domains Positively Regulates Catalysis of the Tec Family Kinases †
Article
  • May 2007
Tec family nonreceptor tyrosine kinases are key immunological enzymes that control processes that range from T and B cell development to reorganization of the actin cytoskeleton. The full-length Tec kinases have been resistant to crystallization. This lack of structural data and the paucity of in vitro biochemical data for this kinase family leave a void in our understanding of Tec kinase regulation. In this report we have used interleukin-2 tyrosine kinase (Itk) as a model system to gain insight into the regulatory apparatus of the Tec kinases. Use of a quantitative in vitro kinase assay has uncovered an essential role for the short linker region flanked by the SH2 and kinase domains of Itk in positively regulating Itk catalytic activity. The precise residues that allosterically regulate Itk are conserved among Tec kinases, pointing to the conserved nature of this regulatory mechanism within the family. These findings indicate that Tec kinases are not regulated in the same manner as the Src kinases but rather share some of the regulatory features of Csk instead.
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Tec family kinases: Itk signaling and the development of NKT αβ and γδ T cells
Article
The Tec family tyrosine kinase interleukin-2 inducible T-cell kinase (Itk) is predominantly expressed in T cells and has been shown to be critical for the development, function and differentiation of conventional αβ T cells. However, less is known about its role in nonconventional T cells such as NKT and γδ T cells. In this minireview, we discuss evidence for a role for Itk in the development of invariant NKT αβ cells, as well as a smaller population NKT-like γδ T cells. We discuss how these cells take what could be the same signaling pathway regulated by Itk, and interpret it to give different outcomes with regards to development and function.
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