The Notch Signaling Pathway

Because stem cell differentiation is controlled by signal transduction pathways, some of my readers have suggested that I discuss particular signal transduction pathways. In the previous post, the Notch signaling pathway was mentioned, and this provides a good reason to introduce my readers to it.

To think of signal transduction, one should consider the popular board game, Mouse Trap. When your game icon lands on the mouse trap spot on the game board, you turn a crank, and this crank rotates a vertical gear that is connected to a gear. Once that gear turns, it pushes lever that is braced with a rubber band until it snaps back and hits a swinging boot. The boot kicks over a bucket, which sends a marble down a rickety staircase. At the bottom of the staircase, the marble enters a chute and eventually taps a vertical pole. At the top of this pole is an open hand (palm-up) that supports another marble. The movement of the pole, caused by the tapping of its base by the first marble knocks the second marble free and it falls through a hole in its platform into a bathtub, and then through a hole in the tub onto one end of a seesaw. The propulsion of the seesaw launches a plastic diver on the other end into a round tub that is on the same base as the barbed pole that supports the mouse cage. The tub’s movement shakes the cage free from the top of the pole and the cage falls to trap the mouse.

This machine that traps the mouse is very similar to signal transduction in cells. The signal to catch the mouse (turning the crank), is far removed from the cage that eventually catches the mouse. Also, the act of catching the mouse (the dropping of the mouse cage), requires the prior execution of many other causally linked steps.

Notch signaling begins with a cell surface protein called Notch. Notch has a large region of the protein outside the cell and a small part of it that intersects the cell membrane, and another region that extends into the cell interior. All three of these domains of the Notch protein play an essential role in the function of Notch.

To turn the crank of this mouse trap, Notch must bind to its receptor. The Notch receptor can be a member of the DSL (Delta, Serrate and Lag-2) gene family.  The receptor is found on the surface of another cell. The binding of Notch to its receptor is the action that “turns the crank” on this mouse trap. Notch binding changes the structure of Notch, and it is clipped into two unequal halves by an enzyme that clips proteins at specific sites (the gamma-secretase). The Notch protein is now broken into a portion that remains anchored in the cell membrane, and another regions that remains inside the cell. This portion of the Notch protein is called “Intracellular Notch” or ICN (Wang MM.Int J Biochem Cell Biol.2011 Nov;43(11):1550-62 & D’Souza B, Miyamoto A, Weinmaster G. Oncogene. 2008 Sep 1;27(38):5148-67).

With the cleavage of Notch, the boot has knocked over the bucket and the marble has moved down the rickety staircase to the chute. ICN is able to enter the cell nucleus. There are proteins in the cytoplasm that can bind to ICN and prevent it from doing so, but we will not discuss them at this time (see van Tetering G, Vooijs M. Curr Mol Med. 2011 Jun;11(4):255-69).

Once in the nucleus, ICN teams up with another protein to activate the express of particular genes. Therefore, what began at the cell surface with the binding of the Notch protein by its receptor had culminated in the changes in gene expression in the nucleus. The other proteins that work together with ICN are members of the “CSL” gene family. CSL stands for “CBF1/RBP-Jκ/Suppressor of Hairless/LAG-1.” When ICN combines with CSL the two proteins are converted from inactive proteins into a complex that actives the synthesis of messenger RNAs for specific genes. This rattles the pole that brings the cage down on the mouse’s head (see Kovall RA. Oncogene. 2008 Sep 1;27(38):5099-109).

What are the target genes of Notch signaling? Great question, but the answer is frustrating, since it depends on the cell type. In developing pancreas, once of the target genes of Notch signaling is PTF1a, but in other cell types and tissues, other genes are activated.

In embryonic stem cells and other stem cells as well, the Notch signaling pathway plays a vital role in the differentiation of these cells into various cell types. Notch signaling is also an important component of the pathology of organ failure in many organs and is also a central pathway involved in the onset and maintenance of several different types of cancers.  Understanding its function and how to regulate it is crucial.