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transducers and adaptor molecules including Gab1, Grb-2, SHC, PI-3 kinase,
PLC-gamma and c-Src (Ponzetto et al., 1994).
Gab proteins comprise a growing family of scaffolding/docking molecules
involved in receptor tyrosine kinase signalling (for a recent review see Liu and
Rohrschneider, 2002). They contain multiple functional motifs that allow
them to mediate interactions with other signalling molecules. Gab1 (Grb2-
associated binder 1), the first mammalian Gab cloned, was originally isolated
as a Grb2-binding protein and is tyrosine phosphorylated in response to
various stimuli (Holgado-Madruga et al., 1996). It was also identified
independently as a Met-receptor interacting protein in a yeast two-hybrid
screen and as the major tyrosine phosphorylated protein in cells transformed
by the Tpr-Met oncogene (Weidner et al., 1996; Fixman et al., 1997). Further
biochemical studies demonstrated that Gab1 is also involved in a number of
other signalling events mediated by interleukin, interferon, erythropoietin and
thrombopoietin receptors. Gab1 contains an N-terminal Pleckstrin homology
domain, a central proline-rich domain and multiple tyrosines within binding
motifs favoured by various SH2-domain-containing proteins. Phosphorylated
Gab1 can bind Grb2, the tyrosine phosphatase SHP2, the p85 subunit of PI-
3K, PLC-gamma and Crk (Liu and Rohrschneider, 2002).
c-Met, SF/HGF and Gab1 control delamination of migrating
muscle precursors from the dermomyotome
The important role that SF/HGF and c-Met play in the development of
migratory muscle precursors was established by a genetic analysis in the mouse
(Bladt et al., 1995) (Figure 20.2). Mutation of the SF/HGF or c-Met gene results
in complete absence of the muscle groups in the mouse embryo that derive from
migrating cells, whereas other muscle groups form. In control embryos,
migrating myogenic progenitors are generated from the dermomyotome by an
epithelial-mesenchymal transition. The migrating cells cannot be observed in
SF/HGF or c-Met null mutant mouse embryos. SF/HGF and c-Met regulate
the detachment and emigration of myogenic precursor cells from the
dermomyotome in vivo, a process that resembles the cellular response that led
to the identification of SF/HGF as 'scatter factor' in cell culture. The c-Met and
SF/HGF mutations do not interfere with development of the dermomyotome
prior to delamination, nor do they impair the establishment of the muscle
precursor pool in the dermomyotome (Dietrich et al., 1999). The mutations
preclude only the dispersal of the migratory progenitors, which are retained
instead in the dermomyotome compartment. Interestingly, during normal
development migratory progenitors are generated from the dermomyotome of
specific somites only. The tight spatio-temporal control of the emigration
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