Figure 15–58 lateral inhibition mediated by Notch and Delta during neural cell development in Drosophila. When individual cells in the epithelium begin to develop as neural cells, they signal to their neighbors not to do the same. This inhibitory, contact-dependent signaling is mediated by the ligand Delta, which appears on the surface of the future neural cell and binds to Notch receptor proteins on the neighboring cells. In many tissues, all the cells in a cluster initially express both Delta and Notch, and a competition occurs, with one cell emerging as winner, expressing Delta strongly and inhibiting its neighbors from doing likewise. In other cases, additional factors interact with Delta or Notch to make some cells susceptible to the lateral inhibition signal and others unresponsive to it.
CYTOSOL 2 3 CYTOSOL Delta signaling cell plasma membrane target cell plasma membrane 9 EGF-like domains TRANSPORT TO PLASMA MEMBRANE BINDING TO DELTA, ENDOCYTOSIS OF DELTA– NOTCH-FRAGMENT COMPLEX, AND CLEAVAGE AT SITE 2 CLEAVAGE AT SITE 3 NOTCH TAIL MIGRATES TO NUCLEUS EXTRACELLULAR SPACE ENDOCYTOSIS
Figure 15–59 The processing and activation of Notch by proteolytic cleavage. The numbered red arrowheads indicate the sites of proteolytic cleavage. The first proteolytic processing step occurs within the trans Golgi network to generate the mature heterodimeric Notch receptor that is then displayed on the cell surface. The binding to Delta on a neighboring cell triggers the next two proteolytic steps: the complex of Delta and the Notch fragment to which it is bound is endocytosed by the Delta-expressing cell, exposing the extracellular cleavage site in the transmembrane Notch subunit. Note that Notch and Delta interact through their repeated EGF-like domains. The released Notch tail migrates into the nucleus, where it binds to the Rbpsuh protein, which it converts from a transcriptional repressor to a transcriptional activator.
in wing development, while in mice, the Int1 gene was found because it promoted the development of breast tumors when activated by the integration of a virus next to it. Both of these genes encode Wnt proteins. Wnts are unusual as secreted proteins in that they have a fatty acid chain covalently attached to their N-terminus, which increases their binding to cell surfaces. There are 19 Wnts in humans, each having distinct, but often overlapping, functions.
Wnts can activate at least two types of intracellular signaling pathways. Our primary focus here is the Wnt/β-catenin pathway (also known as the canonical Wnt pathway), which is centered on the latent transcription regulator β-catenin. A second pathway, called the planar polarity pathway, coordinates the polarization of cells in the plane of a developing epithelium and depends on Rho family GTPases. Both of these pathways begin with the binding of Wnts to Frizzled family cell-surface receptors, which are seven-pass transmembrane proteins that resemble GPCRs in structure but do not generally work through the activation of G proteins. Instead, when activated by Wnt binding, Frizzled proteins recruit the scaffold protein Dishevelled, which helps relay the signal to other signaling molecules.