Visit our Expo - Redox and Inflammation signaling 2012

The Role of Met-Gab1 Signalling in Vivo
Walter BIRCHMEIER, Jolanta CHMIELOWIEC, and Ute SCHAEPER
Max Delbrück Center for Molecular Medicine, Robert-Rössle-Strasse 10, 13125 Berlin,
Germany
We examined wound healing in conditional mutant mice, in which the Met tyrosine kinase,
the receptor of HGF/SF, was ablated in the epidermis. In the Met-deficient epidermis,
keratinocytes were completely unable to contribute to re-epithelialization of the wounds.
However, wound closure could occur by fast proliferation and migration of the few (5%)
remaining wild-type keratinocytes. These results show that the HGF/SF and Met signalling
system, which is not important for normal skin formation and maintenance, is crucial for skin
regeneration.
Gab1 is a signalling protein that belongs to the class of docking proteins, which function
downstream of tyrosine kinases. Gab1 was discovered as a direct target of the tyrosine kinase
c-Met, the receptor for SF/HGF. It was not known, which downstream signalling pathways
are important for Gab1 function in vivo, and what are the in vivo contributions of the c-Met
and Grb2 binding sites for coupling Gab1 to specific tyrosine kinases. To address these
questions, we generated Gab1 knock-in mice that express Gab1 cDNAs, which carry
mutations in the c-Met, Grb2, PI3K or Shp-2 binding sites. Mutant mice display distinct, but
also overlapping phenotypes, which demonstrate that Gab1 acts in several tyrosine kinase
signalling pathways. Of particular importance in vivo is the binding site of Gab1 to the Shp-2
downstream substrate, which is essential for the migration of muscle precursor cells into the
limbs.
- 35 -