Tyrosine Kinases!

Ever heard of the Philadelphia chromosome? How about imatinib or Gleevec, the highly successful miracle drug most famously used to treat CML (chronic myelogenous leukemia)?

If so, you may have heard of my lab’s focus: the Abl family of protein tyrosine kinases.

When I searched through labs in the Department of Pharmacology and Cancer Biology and came across one with the focus of researching the functions the Abl family of tyrosine kinases, the faintly familiar ideas of the Philadelphia chromosome and Gleevec, which I had associated with the Abl gene, caught my attention. The Philadelphia chromosome represents the abnormal translocation in chromosome 22 found in leukemia cancer cells that results in the Bcr-Abl fusion gene. Imatinib, a chemotherapy medication, hinders the Bcr-Abl tyrosine kinase. Thus, I knew that research in the Pendergast lab, which centers on the exploration of Abl kinases, was sure to be interesting.

Each lab member has an individual project that stems from the Abl kinase focus of the Pendergast lab. Several lab members are utilizing mouse models for their projects. Others, actually all members minus me, continually learn and incorporate creative, new techniques to advance their projects. As for me, I am also learning many new techniques, but ones that have been around for much longer… Nevertheless, I am very grateful to my two lab mentors for taking time off of their own individual research projects to guide me and provide me with the tools I need to conduct research in this lab.

My research project builds on the project of the previous undergrad student in the Pendergast lab, who graduated in May. She focused on triple-negative breast cancer cells, in particular. The goal of my project is to define what role Abl kinases have in the signaling of a specific type of receptor tyrosine kinase (protein) in breast and lung cancer cells. Specifically, I am looking into the role of the interaction between Abl kinases and this particular protein in factors such as cell growth, EMT (epithelial-mesenchymal transition), migration, and invasion.

Now, you may be wondering what exactly is a tyrosine kinase? I will start by explaining one of the roles of phosphate groups. When transferred to a specific protein, a phosphate group can activate that protein. Enzymes (proteins) that add phosphate groups to other molecules, thereby activating the molecules, are called kinases. Tyrosine kinases are a subclass of protein kinases in that they possess the amino acid, tyrosine, to which the phosphate group attaches. Abl genes encode protein tyrosine kinases that activate proteins that are involved in factors such as cell growth and development. A continuous activation of proteins that are involved in important cell processes can lead to cancer, which is caused by an abnormal and uncontrolled division of cells.

Now that you hopefully understand some potentially fatal implications of the interactions of the Abl family of tyrosine kinases with other molecules, you may be wondering, how does one choose which proteins to explore in their interaction with Abl kinases? As my PI, Dr. Pendergast, explained to me, a former postdoc in the lab, along with the previous undergrad, who I mentioned earlier, conducted an unbiased screen for Abl2-induced tyrosine phosphorylated targets, which identified a specific set of kinases to be highly phosphorylated Abl targets. Moreover, it has been shown that these particular kinases are upregulated in breast cancer patients who develop resistance to diverse therapies. Thus, it is worthwhile to investigate and analyze the effects of the signaling axis between Abl kinases and these particular proteins.

Question: how many times can one say, “kinase” in a post? Read the above carefully to find out. 🙂

My research project has involved techniques that include culturing of various breast cancer and lung cancer cell lines, viral transductions, loss- and gain-of-function experiments, immunoprecipitations, and of course, western blots, the bread and butter of our research. I can’t wait to learn even more techniques and practice, practice, practice!

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