How cells respond to biochemical signals

August 18, 2011

Researchers at Harvard Medical School have discovered that structural elements in the cell play a crucial role in organizing the motion of cell-surface receptors, which are proteins that enable cells to receive signals from other parts of the organism.

This discovery fills a fundamental gap in the understanding of how cells relate to biochemical signals, including pharmaceuticals, and could have profound implications for drug development and the treatment of cancer and other diseases, the researchers said.

The researchers studied the motion of CD36, a receptor in human macrophages, a type of white blood cell that plays a role in immune response. CD36 detects oxidized LDL (oxLDL), a lipoprotein implicated in atherosclerosis.

Like many receptors, CD36 can’t work alone; a group of receptors must cluster together to send a signal into the cell. Until now, very little was known about how those functional groups of receptors formed. The cell and receptors were thought to wait “at rest” until a chemical signal happened to appear, causing receptors to coalesce.

This study reveals a much more dynamic “before” picture, with structures that precondition the cell to respond to signals. The researchers say that their work clearly demonstrates how “resting” receptor movements are functionally relevant to the transmission of signals into the cell.

Using an automated particle-tracking algorithm, the researchers analyzed single-molecule movies — in live cells and in real time under a microscope — to dissect the receptor behavior and its regulation.

The movies reveal three kinds of motion by the receptors, which are sensitive to strands of the cytoskeleton’s actin meshwork adjacent to the cell surface. As receptors roam about, they bump into these strands, slowing, stopping or changing direction. Some wander freely about the surface of the cell. Others become temporarily stuck inside a pocket of the mesh, as if trapped in a cage. Finally, some of the receptors travel linear paths.

These paths follow elongated “corridors” alongside the cell’s microtubules, another part of the cell’s cytoskeleton, radiating in more-or-less straight lines from the nucleus. In these narrow corridors free of actin strands, receptors move with more freedom, regularly bumping into one another, and forming clusters that stick together fleetingly and then drift apart.

The researchers suspected that these pre-formed clusters aid in signaling, so they tested a theory that these pre-formed clusters aid in signaling. They disrupted the cytoskeleton and found that when the corridors disappeared, the cell no longer responded effectively to oxLDL.

Ref.: Khuloud Jaqaman, et al., Cytoskeletal Control of CD36 Diffusion Promotes Its Receptor and Signaling Function, Cell, 2011; [DOI: 10.1016/j.cell.2011.06.049]