Protein tyrosine kinase 6 (PTK6) is an intracellular tyrosine kinase that contains SH3 and SH2 domains, but lacks an SH4 domain that promotes membrane localization. Lack of membrane targeting facilitates flexibility in its intracellular localization and access to substrates. In differentiated prostate epithelial cells, PTK6 is primariy found in the nucleus. However, active PTK6 associates with the plasma membrane in prostate cancer, and its increased expression is correlated with metastasis and poor survival. We found that membrane-associated PTK6 promotes cell transformation, the epithelial mesenchymal transition, and tumor cell metastasis, while nuclear PTK6 inhibits growth. We designed a collaborative proposal to address the question, How is PTK6 recruited to the plasma membrane where it promotes tumorigenesis? Our preliminary data suggest PTK6 directly binds phosphate-rich lipids, including phosphatidylinositol-(3, 4, 5)-trisphosphate (PIP3), at the plasma membrane. Increased production of PIP3 is commonly observed in cancer due to activation of PI3K and/or mutation of the tumor suppressor lipid phosphatase PTEN. We hypothesize that phosphate-rich lipids, such as PIP3 regulate the recruitment and activation of PTK6 at the plasma membrane to drive tumorigenesis and metastases. Highly synergistic studies proposed by Dr. Tyner, a cell biologist, and Dr. Gaponenko, a structural biochemist, use an array of biochemical, biophysical, molecular, genetic and cell biology approaches to: (i) Investigate PTK6 lipid binding; (ii) Identify domains in PTK6 required for lipid binding; (iii) Determine contributions of PI3K/PTEN/PIP3 to activation of PTK6 at the membrane in prostate cancer cells; and (iv) Examine contributions of PTK6 membrane binding to prostate tumorigenesis in mice with prostate specific deletion of the gene encoding the tumor suppressor PTEN. The results of this research will define a novel mechanism for intracellular tyrosine kinase membrane targeting and activation, and could identify novel strategies to inhibit PTK6 in cancer. In additio, alterations in PTK6 intracellular localization or expression may provide a unique marker for staging prostate cancers.

Public Health Relevance

The intracellular tyrosine kinase Protein Tyrosine Kinase 6 (PTK6) in preferentially localized to the cell plasma membrane in mouse and human prostate tumors, and targeting active PTK6 to the membrane promotes prostate tumorigenesis and metastases. New preliminary findings suggest that PTK6 associates with the membrane through a novel mechanism of direct lipid binding. We will explore this novel mechanism and its impact on cancer signaling, since understanding how PTK6 is regulated could lead to development of treatments that prevent or delay prostate tumor progression.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA188427-02
Application #
9053459
Study Section
Molecular and Integrative Signal Transduction Study Section (MIST)
Program Officer
Knowlton, John R
Project Start
2015-05-01
Project End
2020-04-30
Budget Start
2016-05-01
Budget End
2017-04-30
Support Year
2
Fiscal Year
2016
Total Cost
Indirect Cost
Name
University of Illinois at Chicago
Department
Biochemistry
Type
Schools of Medicine
DUNS #
098987217
City
Chicago
State
IL
Country
United States
Zip Code
60612
Wang, Guanqiao; Zhang, Mingzhen; Jang, Hyunbum et al. (2018) Interaction of Calmodulin with the cSH2 Domain of the p85 Regulatory Subunit. Biochemistry 57:1917-1928
Abdelkarim, Hazem; Marshall, Michael S; Scesa, Giuseppe et al. (2018) ?-Synuclein interacts directly but reversibly with psychosine: implications for ?-synucleinopathies. Sci Rep 8:12462
Gao, Xianlong; Abdelkarim, Hazem; Albee, Lauren J et al. (2018) Partial agonist activity of ?1-adrenergic receptor antagonists for chemokine (C-X-C motif) receptor 4 and atypical chemokine receptor 3. PLoS One 13:e0204041
Gao, Xianlong; Albee, Lauren J; Volkman, Brian F et al. (2018) Asymmetrical ligand-induced cross-regulation of chemokine (C-X-C motif) receptor 4 by ?1-adrenergic receptors at the heteromeric receptor complex. Sci Rep 8:2730
Albee, Lauren J; LaPorte, Heather M; Gao, Xianlong et al. (2018) Identification and functional characterization of arginine vasopressin receptor 1A : atypical chemokine receptor 3 heteromers in vascular smooth muscle. Open Biol 8:
Procter, Dean J; Banerjee, Avik; Nukui, Masatoshi et al. (2018) The HCMV Assembly Compartment Is a Dynamic Golgi-Derived MTOC that Controls Nuclear Rotation and Virus Spread. Dev Cell 45:83-100.e7
Hitchinson, Ben; Eby, Jonathan M; Gao, Xianlong et al. (2018) Biased antagonism of CXCR4 avoids antagonist tolerance. Sci Signal 11:
Biancucci, Marco; Minasov, George; Banerjee, Avik et al. (2018) The bacterial Ras/Rap1 site-specific endopeptidase RRSP cleaves Ras through an atypical mechanism to disrupt Ras-ERK signaling. Sci Signal 11:
Halasi, Marianna; Hitchinson, Ben; Shah, Binal N et al. (2018) Honokiol is a FOXM1 antagonist. Cell Death Dis 9:84
Albee, Lauren J; Eby, Jonathan M; Tripathi, Abhishek et al. (2017) ?1-Adrenergic Receptors Function Within Hetero-Oligomeric Complexes With Atypical Chemokine Receptor 3 and Chemokine (C-X-C motif) Receptor 4 in Vascular Smooth Muscle Cells. J Am Heart Assoc 6:

Showing the most recent 10 out of 22 publications