Basic—Alimentary TractInduction of Protein Tyrosine Kinase 6 in Mouse Intestinal Crypt Epithelial Cells Promotes DNA Damage–Induced Apoptosis
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Animals and Tissues
Ptk6-null mice (B6.129SV-Ptk6tm1Aty) have been previously described.13 Sex- and age-matched male mice at 8–10 weeks of age from heterozygous Ptk6+/− breeding pairs were used. Samples from multiple animals of the same genotype are included in each figure. Whole-body irradiation was performed using a 137Caesium γ-source (J. L. Shepherd model 6810; J. L. Shepherd, San Fernando, CA) at a dose of 8 Gy. At 0, 6, and 72 hours following irradiation, the mice were killed by co2 anesthesia followed by
PTK6 Expression Is Induced in Intestinal Crypts After γ-Irradiation
To begin to assess the role of PTK6 following DNA damage, PTK6 protein levels were examined by immunoblotting in the small intestines of wild-type mice following total body γ-irradiation (8 Gy). A significant time-dependent increase in PTK6 protein levels was detected after irradiation (Figure 1A and B). PTK6 protein expression was localized in untreated and irradiated wild-type mice using immunohistochemistry. Consistent with prior reports,13 PTK6 protein expression was primarily restricted to
Discussion
Functions of PTK6 are not well understood and often seem paradoxical. A variety of data indicate that this intracellular tyrosine kinase has distinct activities in different cell types. Although PTK6 expression is associated with differentiation in the gastrointestinal tract and skin,3, 5, 6, 13 it is expressed at relatively high levels in a high percentage of human breast tumors but not in the normal mammary gland.9 In the normal prostate, PTK6 is localized to nuclei of epithelial cells but is
Acknowledgments
A.H.'s current address is: Bayer Schering Pharma AG, GDD, TCR in vivo 3, Muellerstr. 178, 13353 Berlin, Germany.
References (46)
- et al.
Differential expression of the non-receptor tyrosine kinase BRK in oral squamous cell carcinoma and normal oral epithelium
Oral Oncol
(2004) - et al.
Expression and oncogenic role of Brk (PTK6/Sik) protein tyrosine kinase in lymphocytes
Am J Pathol
(2006) - et al.
The nuclear tyrosine kinase BRK/Sik phosphorylates and inhibits the RNA-binding activities of the Sam68-like mammalian proteins SLM-1 and SLM-2
J Biol Chem
(2004) - et al.
Wnt signaling, lgr5, and stem cells in the intestine and skin
Am J Pathol
(2009) - et al.
Regulated association of protein kinase B/Akt with breast tumor kinase
J Biol Chem
(2005) - et al.
AKT/PKB signaling: navigating downstream
Cell
(2007) - et al.
Bad, a heterodimeric partner for Bcl-XL and Bcl-2, displaces Bax and promotes cell death
Cell
(1995) - et al.
Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery
Cell
(1997) - et al.
p90(RSK) blocks bad-mediated cell death via a protein kinase C-dependent pathway
J Biol Chem
(1999) - et al.
Rsk1 mediates a MEK-MAP kinase cell survival signal
Curr Biol
(2000)
Serine phosphorylation of death agonist BAD in response to survival factor results in binding to 14-3-3 not BCL-X(L)
Cell
Tissue damage-induced intestinal stem cell division in Drosophila
Cell Stem Cell
Apoptosis of human intestinal epithelial cells after bacterial invasion
J Clin Invest
Brk, Srm, Frk, and Src42A form a distinct family of intracellular Src-like tyrosine kinases
Oncol Res
Tyrosine kinase gene expression in the mouse small intestine
Oncogene
A novel intracellular epithelial cell tyrosine kinase is expressed in the skin and gastrointestinal tract
Oncogene
BRK/Sik expression in the gastrointestinal tract and in colon tumors
Clin Cancer Res
A role for the epithelial-cell-specific tyrosine kinase Sik during keratinocyte differentiation
Proc Natl Acad Sci U S A
Role of breast tumour kinase in the in vitro differentiation of HaCaT cells
Br J Dermatol
Altered localization and activity of the intracellular tyrosine kinase BRK/Sik in prostate tumor cells
Oncogene
BRK tyrosine kinase expression in a high proportion of human breast carcinomas
Oncogene
The BRK tyrosine kinase is expressed in high-grade serous carcinoma of the ovary
Cancer Biol Ther
Protein tyrosine kinase 6 negatively regulates growth and promotes enterocyte differentiation in the small intestine
Mol Cell Biol
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2023, International ImmunopharmacologyTargeting protein tyrosine kinase 6 in cancer
2020, Biochimica et Biophysica Acta - Reviews on CancerCitation Excerpt :PTK6 expression is induced by a variety of cellular stresses including DNA damage [49,50], hypoxia, and reactive oxygen species [45]. PTK6 expression is induced in the proliferating progenitor cell compartments of the intestine and skin after DNA-damage generated by different mechanisms, including gamma [49,50] and UV [51] irradiation and DNA-damaging drugs [50,52]. In cancer cells, PTK6 expression increased following treatment with radiation and chemotherapeutic agents, including doxorubicin [50], Taxol, 5′ fluorouracil [46], and gemcitabine [53].
Protein Tyrosine Kinase 6 Regulates UVB-Induced Signaling and Tumorigenesis in Mouse Skin
2015, Journal of Investigative DermatologyTracing the footprints of the breast cancer oncogene BRK - Past till present
2015, Biochimica et Biophysica Acta - Reviews on CancerCitation Excerpt :A subsequent study corroborated BRK expression specifically in the differentiating epithelial cells of the colon in the gastrointestinal (GI) tract [22]. However, later studies by the same group revealed the induction of BRK expression even in the proliferating epithelial cells of the crypt compartment besides the non-proliferating differentiated epithelial cells of the villi upon exposure to ionizing radiation [80]. Concordantly, it has been reported that under normal conditions BRK is primarily confined to the non-dividing differentiated intestinal cells but becomes induced in the proliferating crypt epithelial cells upon treatment with the carcinogen Azoxymethane (AOM) [81].
Identification of PTK6, via RNA sequencing analysis, as a suppressor of esophageal squamous cell carcinoma
2012, GastroenterologyCitation Excerpt :Finally, through functional studies using overexpression and suppression lentiviral-based expression systems, we found down-regulation of PTK6 to promote tumorigenicity and metastasis through an altered Akt/GSK3β/β-catenin signaling pathway. This finding is also partly in line with past studies by Haegebarth et al, who found PTK6 to have growth-repressing signaling activity via Akt and Wnt signaling.10,11 Interestingly, past studies by Derry et al found that intracellular localization, not the level of PTK6 expression, is the main alteration in PTK6 occurring during the progression of prostate cancer.9
Disruption of the mouse protein tyrosine kinase 6 gene prevents STAT3 activation and confers resistance to azoxymethane
2011, GastroenterologyCitation Excerpt :However, a significant increase in apoptosis was detected in Ptk6+/+ mice compared with Ptk6−/− mice at the 6-hour time point after AOM treatment (Figure 3B and C). These data are consistent with prior reports that PTK6 expression plays an important role in DNA-damage−induced apoptosis in the small intestinal epithelium.10 Immunoblotting also revealed higher levels of cleaved caspase-3 at 6 hours post AOM injection in wild-type mice (Figure 3D).
Conflicts of interest The authors disclose no conflicts.
Funding Supported by National Institutes of Health grants DK44525 and DK068503 (to A.L.T.). A.H. received support from the German Academic Exchange Service (DAAD) and the Schering Foundation. J.J.G. is supported by an American Gastroenterological Association Foundation Graduate Student Research Fellowship Award and was supported by a National Research Service Award/National Institutes of Health institutional T32 training grant, “Training Program in Signal Transduction and Cellular Endocrinology” (T32 DK07739), from the National Institute of Diabetes and Digestive and Kidney Diseases.