The Questions of Developmental Biology

MEK is itself a kinase, which activates ERK by phosphorylation. And ERK is a kinase
that can enter the nucleus and phosphorylate certain transcription factors. This pathway is critical
in numerous developmental processes.
In the migrating neural crest cells of humans and mice, the RTK pathway is important in
activating the microphthalmia transcription factor (Mitf) to produce the pigment cells. We have
been following the Mitf transcription factor for the past two chapters. It is transcribed in the
pigment-forming melanoblast cells that migrate from the neural crest into the skin and in the
melanin-forming cells of the pigmented retina. But we have not yet discussed what proteins
signal this transcription factor to become active. The clue lay in two mouse mutants whose
phenotypes resemble those of mice homozygous for microphthalmia mutations. Like those mice,
homozygous White mice and homozygous Steel mice are white because their pigment cells have
failed to migrate. Perhaps all three genes (Mitf,Steel, and White) are on the same developmental
pathway. In 1990, several laboratories demonstrated that the Steel gene encodes a paracrine
protein called stem cell factor (see Witte 1990). Stem cell factor
binds to and activates the Kit receptor tyrosine kinase encoded
by the White gene (Spritz et al. 1992; Wu et al. 2000). The
binding of stem cell factor to the Kit RTK dimerizes the Kit
protein, causing it to become phosphorylated. The
phosphorylated Kit activates the pathway whereby
phosphorylated ERK is able to phosphorylate the Mitf
transcription factor (Hsu et al. 1997; Hemesath et al. 1998). Only
the phosphorylated form of Mitf is able to bind the p300/CBP
coactivator protein that enables it to activate transcription of the
genes encoding tyrosinase and other proteins of the melaninformation
pathway (Figure 6.15; Price et al. 1998).
The Smad pathway
Members of the TFG-β superfamily of paracrine factors activate members of the Smad
family of transcription factors (Figure 6.20; Heldin et al. 1997). The TGF-β ligand binds to a type
II TGF-β receptor, which allows that receptor to bind to a type I TGF-β receptor. Once the two
receptors are in close contact, the type II receptor phosphorylates a serine or threonine on the type
I receptor, thereby activating it. The activated type I receptor can now phosphorylate the Smad
proteins. (Researchers named the Smad proteins by eliding the names of the first identified