The Questions of Developmental Biology

members of this family: the C. elegans Sma protein and the Drosophila Mad protein.) Smads 1
and 5 are activated by the BMP family of TGF-β factors, while the receptors binding activin and
the TGF-β family phosphorylate Smads 2 and 3. These phosphorylated Smads bind to Smad 4
and form the transcription factor complex that will enter the nucleus. In vertebrates, the TGF-β
superfamily ligand Nodal appears to activate the Smads pathway in those cells responsible for the
formation of the mesoderm and for specifying the left-right axis in vertebrates (Graff et al. 1996;
Nomura and Li 1998).
The JAK-STAT pathway
Another important pathway transducing information on the cell membrane to the nucleus
is the JAK-STAT pathway. Here the set of transcription factors consists of the STAT (signal
transducers and activators of transcription) proteins (Ihle 1995Ihle 1996). STATs are
phosphorylated by certain receptor tyrosine kinases, including fibroblast growth factor receptors
and the JAK family of tyrosine kinases. The JAK-STAT pathway is extremely important in the
differentiation of blood cells and in the activation of the casein gene during milk production
(Briscoe et al. 1994; Groner and Gouilleux 1995). The role of this pathway in casein production is
shown in Figure 6.21. Here, the endocrine factor prolactin binds to the extracellular regions of
prolactin receptors, causing them to dimerize. A JAK protein kinase is bound to each of the
receptors (in their respective cytoplasmic regions), and these JAK proteins are now brought
together, where they can phosphorylate the receptors at several sites. The receptors are now
activated and have their own protein kinase activity. Therefore, the JAK proteins convert a
receptor into a receptor tyrosine kinase. The activated receptors can now phosphorylate particular
inactive STATs and cause them to dimerize. These dimers are the active form of the STAT
transcription factors, and they are translocated into the nucleus, where they bind to specific
regions of DNA. In this case, they bind to the upstream promoter elements of the casein gene,
causing it to be transcribed.