A tale of two SHEPherds

By Heather Buschman, Ph.D.
October 18, 2010

A paper published online this week in the Proceedings of the National Academy of Sciences (PNAS) highlights a collaboration between two Sanford-Burnham scientists, one an immunologist in the Infectious and Inflammatory Disease Center and the other a cell communication expert in the Cancer Center.

Dr. Robert Rickert studies B cells, a type of white blood cell in the immune system that produces antibodies to neutralize foreign particles. Because they move around the body, immune cells are oddities compared to other types of cells.

“Other scientists worry about a process called anoikis, in which wandering cells are programmed to self-destruct,” Dr. Rickert explains. “In contrast, only some populations of B cells stay put, like those found in the marginal zone of the spleen.”

So it caught his attention one day when he heard his colleague Dr. Elena Pasquale talk about her work on integrins, a family of proteins located on the surface of many cell types. Integrins carry signals back and forth between the inside and outside of cells, allowing cells to adhere to their surroundings or other cells. Dr. Rickert knew that integrin signaling is required for B cells to remain in a particular region of the spleen, known as the marginal zone, but not why.

Meanwhile, Dr. Pasquale was already thinking about enlisting Dr. Rickert’s help. To determine the function of SHEP1, a protein important in the integrin signaling pathway, her laboratory created a strain of mice that lack SHEP1. Then they looked for differences between these mice and normal mice expecting to find defects in the three main regions where SHEP1 is present at high levels: the brain, blood vessels and the immune system.

“We followed up on SHEP1 function in the brain and blood vessels, but the immune system is not really my area of expertise,” says Dr. Pasquale. “So we asked the Rickert laboratory if they might be interested in taking a look at the mice.”

They were. In the PNAS paper published this week, the Rickert and Pasquale laboratories untangle some of the molecular details linking SHEP1 and marginal zone B cells. They show that B cells lacking SHEP1 develop normally, but far fewer are found in the marginal zone of the spleen. That means that either B cells can’t migrate to the marginal zone or they get there and don’t stay. Normally, B cells located in the spleen sample the blood as it passes through, looking for foreign particles like bacteria. Without this population of B cells, the mice cannot fight infections as well as normal mice.

Probing further, the researchers found that when SHEP1 is functioning properly, it activates another integrin signaling protein called CasL. Since CasL is known to influence immune cell adhesion and movement, it makes sense that this protein also keeps B cells in the marginal zone.

“This study is interesting because it came out of fundamental insights from two different systems – B cell development and integrin signaling – that happen to depend on the same molecule,” Dr. Rickert says.

Next Drs. Rickert and Pasquale will team up with Dr. Stefan Riedl to study the structure of the SHEP1-CasL complex. Understanding how different regions of this complex could be activated or inhibited might provide further insight into its function.

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Heather Buschman, Ph.D.

Heather was an SBP Communications staff member.



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