Dr. Angela L. Tyner
Professor
- UIC University Scholar (2017-2020)
- PhD, University of Chicago
- Postdoctoral Training, Princeton University
Major Interests:
Tyrosine Kinase Signaling in Normal Epithelia and Cancer
PTK6, a Regulator of Epithelial Differentiation Our efforts to identify novel regulatory genes that control the rapid renewal of the intestinal epithelium resulted in the cloning of a gene encoding an intracellular protein tyrosine kinase named Protein Tyrosine Kinase 6 (PTK6; also called Sik for Src-related intestinal kinase, and BRK for Breast tumor kinase). PTK6 is expressed in differentiated cells in the linings of the gastrointestinal tract (tongue, esophagus, stomach, small and large intestine) and skin (Figure 1). In the intestine, kinase-dependent and independent functions of PTK6 contribute to epithelial cell differentiation and turnover and help to maintain the epithelial phenotype of colon cancer. Using animal models and organoid cultures we are exploring roles of PTK6 in the differentiation of specific epithelial cell lineages in the gastrointestinal tract.
Figure 1: PTK6 is expressed in differentiated cells in the mouse small intestine. PTK6 antibody binding is visualized with DAB (brown).
Figure 2:PTK6 is activated in specific cells at the plasma membrane in prostates from mice with conditional disruption of Pten in prostate (PB-Cre4;Ptenfl/fl, right panels). Pten is expressed in Ptenfl/fl mice without Cre4 recombinase (left panels). Immunostaining with antibodies for total (brown, DAB) and active PTK6 (PY342, green) is shown.
Figure 3: Inhibition of PTK6 by vemurafenib. A) PC3 prostate cancer cells expressing active membrane targeted Palm-PTK6-YF were treated with 1 µM vemurafenib for one hour. PTK6 activation (PY342) and activation of its downstream target ERK1/2 (PT202/Y204) was inhibited. B, C) Growth of flank xenograft tumors produced by cells in A (PC3 control vector and Palm-PTK6-YF) was inhibited in vivo by the vemurafenib analogue PLX4720. Both endogenous PTK6 and ectopic Palm-PTK6-YF are inhibited, leading to reduced tumor growth (from Wozniak, et al., 2019).
PTK6 in Cancer PTK6 is induced in a variety of cancers including breast, prostate, and pancreatic cancer (reviewed in Gilic and Tyner, 2020). PTK6 is expressed in nuclei of normal prostate epithelial cells, but relocalized to the cytoplasm and membrane in prostate tumors. Loss of the tumor suppressor protein PTEN, a frequent event in advanced prostate cancer, leads to activation of PTK6 at the plasma membrane (Wozniak et al., 2017 and Zheng et al, 2013) (Figure 2). Activation of PTK6 at the plasma membrane in prostate cells promotes the epithelial mesenchymal transition and cancer metastasis. We showed that the kinase inhibitor vemurafenib directly inhibits PTK6 and impairs xenograft prostate tumor growth (Wozniak et al., 2019) (Figure 3). Current studies are directed toward investigating mechanisms by which PTK6 promotes prostate cancer progression and the utility of targeting PTK6 alone and in combination with other agents as a means of cancer treatment. .
Context Specific Functions of PTK6
PTK6 is an intracellular tyrosine kinase distantly related to the SRC family. Although it lacks myristoylation/palmitoylation and a nuclear localization signal, PTK6 can be found in all cellular compartments and its intracellular localization influences its context specific functions. Active PTK6 is oncogenic when it is at the plasma membrane, but it inhibits growth in the nucleus. We are using genetic, cell biology, biochemical and biophysical approaches to study regulation of PTK6 intracellular localization.
Selected Publications
1. Gilic, M.B. and A.L. Tyner, Targeting ProteinTyrosine Kinase 6 in cancer. Biochim Biophys Acta Rev Cancer, 2020. 1874(2): p. 188432.
2. Alwanian, W.M. and A.L. Tyner, Protein Tyrosine Kinase 6 signaling in prostate cancer. Am J Clin Exp Urol, 2020. 8(1): p. 1-8.
3. Wozniak, D.J., et al., Vemurafenib Inhibits Active PTK6 in PTEN-null Prostate Tumor Cells. Mol Cancer Ther, 2019. 18(5): p. 937-946..
4. Wozniak, D.J., et al., PTEN is a protein phosphatase that targets active PTK6 and inhibits PTK6 oncogenic signaling in prostate cancer. Nat Commun, 2017. 8(1): p. 1508.
