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Fundamentals of Cancer Medicine

The Molecular Perspective: c-Abl Tyrosine Kinase

Correspondence: David S. Goodsell, Ph.D., Associate Professor, The Scripps Research Institute, Department of Molecular Biology, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA. Telephone: 858-784-2839; Fax: 858-784-2860; e-mail: goodsell{at}scripps.edu; Web-site: http://www.scripps.edu/pub/goodsell

Received August 18, 2005; accepted for publication August 18, 2005.

	LEARNING OBJECTIVES

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After completing this course, the reader will be able to:

1. Discuss c-Abl and Bcr-Abl and their role in cancer chemotherapy.
   

Phosphate groups are widely used for transmitting signals inside cells. Phosphate has a number of advantages in molecular signaling. With its strong charge and numerous opportunities for hydrogen bonding, it is particularly easy to recognize. Phosphate groups are also readily added to and removed from signaling molecules, using the cell’s ready supply of ATP to power the process. Phosphate groups may be added to small molecules to create characteristic molecules like cyclic AMP. They may also be added to proteins, changing their surface features or even modulating the activity of an enzyme.

As you can imagine, however, one phosphate group looks much like every other one. To be useful in signaling, the phosphate groups must be attached in the proper place and at the proper time. To perform this function, our cells have more than 500 different protein kinases, each designed to add phosphates to a different set of proteins. These many kinases are involved in a complex, interconnected network of signaling, requiring careful control so that each kinase is activated only when its particular signal is needed.

The c-Abl tyrosine kinase, shown in Figure 1, transmits messages about the adhesion of cells to their neighbors and messages indicating when it is time to grow or move to a new location. Like other members of the src family of protein kinases, c-Abl uses a complex conformational change to turn its kinase activity on and off. It is comprised of several domains connected by flexible linkers, including two small regulatory domains, a larger kinase domain, and several additional domains that bind to DNA and actin. In the inactive form, the protein folds into a tight ball with regulatory domains bound to the back of the kinase domain. Because kinases typically must open and close during their catalytic cycles to allow substrates to enter the active site, this compact structure shuts down the enzyme. c-Abl is activated by other proteins in the signaling pathway that interact with the regulatory domains and release them from the kinase domain. Then the kinase is free to move and start adding phosphate groups to its signaling recipients.

View larger version (49K): [in this window] [in a new window]   Figure 1. c-Abl tyrosine kinase. The inactive c-Abl tyrosine kinase is shown at the top, with the regulatory domains in tan and the kinase in green. A long flexible arm (shown schematically because it was not seen in the structure) reaches around, inserting a myristoyl group (red) into a small pocket in the kinase domain and locking the tightly closed complex in place. The site of binding of imatinib is shown in blue, in the kinase domain. At the bottom, the active form is shown. The regulatory domains have been released through binding to other signaling partners (not shown here). Note that this crystal structure does not include the DNA-binding and actin-binding domains found at the C-terminal end of the protein chain. Coordinates were taken from entry 1opk at the Protein Data Bank (http://www.pdb.org).

View larger version (134K): [in this window] [in a new window]   Figure 2. Bcr-Abl in action. The large tetrameric complex of Bcr-Abl is shown at the center, with the Bcr portion in purple and the Abl portion in red. Both the Bcr and Abl kinases are shown acting on other signaling proteins (shown in yellow). A normal, inactive Abl protein is shown at upper right for comparison.

The unfortunate aspects are twofold. First, because there is a huge new piece of protein appended to the end of c-Abl, the regulatory domains don’t work any longer, and the kinase is allowed to function without control. Second, because four Bcr-Abl chains are tethered in close proximity, it is easy for the kinase domains to add phosphates to neighboring Bcr-Abl chains in the tetramer, further activating them. The result is a hyperactive kinase that sends a continuous signal. In leukemia, this promotes the uncontrolled growth of blood cells.

Fortunately, this system is perfect for control by chemotherapy. The disease state is caused (in large part) by an overactive enzyme, so a drug that blocks this enzyme will fight the disease. The drug imatinib was designed for exactly this function—to block the overactive Bcr-Abl fusion protein. When it was tested, it did just that. Butnature always throws hurdles in the path; in advanced cases, these leukemias multiply so quickly that they are able to build up mutations to block the binding of the drug, developing resistant strains.

	DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST

Top Learning objectives Disclosure of potential... Additional reading

 
The author indicates no potential conflicts of interest.

	ADDITIONAL READING

Top Learning objectives Disclosure of potential... Additional reading

 

Hernandez SE, Krishnaswami M, Miller AL et al. How do Abl family kinases regulate cell shape and movement? Trends Cell Biol 2004;14:36–44.[CrossRef][Medline]

Nagar B, Hantschel O, Young MA et al. Structural basis for the autoinhibition of c-Abl tyrosine kinase. Cell 2003;112:859–871.[CrossRef][Medline]

Ren R. Mechanisms of BCR-ABL in the pathogenesis of chronic myelogenous leukemia. Nat Rev Cancer 2005;5:172–183.[CrossRef][Medline]

Sawyers CL. Opportunities and challenges in the development of kinase inhibitor therapy for cancer. Genes Dev 2003;17:2998–3010.[Free Full Text]

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