Signal Transduction Program
Notch
The Notch family of receptors is crucial for stem cell maintenance, and for the differentiation (change of structure or function) of cells during fetal and postnatal development. Amplified Notch signaling, via the overexpression of Notch ligands or the constitutive activation of the receptors, has been shown to result in the development of cancers (leukemias and lymphomas) derived from the T cells of the human immune system.
Introduction
Notch proteins constitute a family of evolutionarily conserved transmembrane receptors, found in organisms as diverse as worms and humans, which function as transcription factors. These are fascinating proteins as they are involved in many differentiation processes and (tissue) lineage decisions in fetal and postnatal development, as well as being implicated in the self-renewal of tissues in organs such as the skin, the gut and the hematopoietic (blood) system. Stem cell maintenance, cell fate decisions and the initiation of cell differentiation are among the many key functions controlled by Notch signaling, and many of these functions are deregulated during tumorigenesis.
Notch Family and Ligands
Mammals have four Notch receptors, Notch1 - 4, which are activated by two distinct and equally conserved cell surface ligands called Delta and Serrate in Drosophila melanogaster (fruit flies). Mammals have five ligands: Jagged1 and Jagged2, which are equivalents (homologues) of Serrate; and Delta1, Delta3 and Delta4, which are homologues of Delta. The receptors and the ligands are expressed on many cell types in various organs of the body.
Notch Function
Notch1 function in mouse skin (more...)
Following activation by ligand binding, the Notch receptor undergoes proteolytic processing, and the functional Notch protein fragment is translocated to the nucleus where it interacts with a transcription factor complex to express Notch target genes.
LICR investigators at the Lausanne Branch are studying the role of Notch receptor and ligand family members in self-renewing organs, such as the hematopoietic system and the skin, by means of conditional gene targeting in the mouse. Using this system, the LICR team showed that the Notch1 receptor is essential for T cell development, and furthermore is involved in determining cell fate, specifically whether a bone marrow progenitor cell becomes a T cell or a B cell. Notch1-deficient bone marrow progenitor cells develop into B cells by default. Thus, at this particular level, Notch1 acts as a lineage-specifier. LICR investigators have also shown that Notch1 signaling is also involved in regulating later T cell development. The molecular mechanisms and downstream targets through which Notch1 signaling exerts its essential functions during T cell development, and whether Notch1 acts as a lineage-specifier in epithelial tissues are currently under investigation.
Notch in Cancer
The first mammalian homologue of Drosophila Notch was identified in patients with T cell acute lymphoblastic leukemia. Since then multiple Notch receptors and ligands have been found to be aberrantly expressed in various human carcinomas leading to a model for Notch function in cancer based on the ability of Notch to maintain normal precursor cells in a proliferating and undifferentiated state.
In contrast to the previously established role of Notch1 as an oncogene in the hematopoietic system, LICR investigators have now also identified Notch1 as a tumor suppressor in mouse skin. Inactivation of Notch1 in the skin led first to hyperproliferation (increased cell growth and division) of the epidermal cells, which was then followed by the development of skin tumors.
The work of LICR, and other, investigators has shown that Notch has multiple facets; one that specifies cell fates, one that promotes tumor growth and another that suppresses tumor growth. Which of these facets is shown appears to be dependent on the cellular context and cross talk with other signal transduction pathways. LICR scientists are working to uncover the mechanisms which lead to these apparently contradictory functions of Notch signaling, in order to devise strategies that interfere with this pathway for therapeutic purposes.
Key Publications
- Radtke F. and Raj K. The role of Notch in tumorigenesis: oncogene or tumour suppressor? Nature Reviews in Cancer 10:756-767, 2003.
- Radtke F., Wilson A., Stark G., Bauer M., van Meerwijk J., MacDonald H.R., Aguet M. Deficient T cell fate specification in mice with an induced inactivation of Notch1. Immunity 10:547-558, 1999.
- Wilson A., MacDonald H.R. and Radtke F. Notch 1-deficient common lymphoid precursors adopt a B cell fate in the thymus. Journal of Experimental Medicine 194:1003-12, 2001.
- Wolfer, A., Wilson, A., Nemir, M., MacDonald, H.R. and Radtke, F. Inactivation of Notch1 impairs VDJbeta rearrangement and allows pre-TCR-independent survival of early alpha beta Lineage Thymocytes. Immunity 16:869-79, 2002.
- Wolfer A., Bakker T., Wilson A., Nicolas M., Ioannidis V., Littman D.R., Lee P.P., Wilson C.B., Held W., MacDonald H.R., Radtke F. Inactivation of Notch 1 in immature thymocytes does not perturb CD4 or CD8 T cell development. Nature Immunology 2:235-41, 2001.
- Rangarajan A., Talora C., Okuyama R., Nicolas M., Mammucari C., Oh H., Aster J.C., Krishna S., Metzger D., Chambon P., Miele L., Aguet M., Radtke F., Dotto G.P. Notch signaling is a direct determinant of keratinocyte growth arrest and entry into differentiation. EMBO Journal 20:3427-36, 2001.
- Nicolas, M., Wolfer A., Raj K., Kummer J.A., Mill P., van Noort H., Hui C.C., Clevers H., Dotto G.P., Radtke F. Notch1 functions as a tumor suppressor in mouse skin. Nature Genetics 33:416-21, 2003.