Genetic evidence that Shp-2 tyrosine phosphatase is a signal enhancer of the epidermal growth factor receptor in mammals.
By using both genetic and biochemical approaches, we have investigated the physiological role of Shp-2, a cytoplasmic tyrosine phosphatase with two Src homology 2 domains, in signaling pathways downstream of epidermal growth factor receptor (EGF-R). In previous studies, a targeted deletion mutation in the SH2-N domain of Shp-2 was introduced into the murine Shp-2 locus, which resulted in embryonic lethality of homozygous mutant (Shp-2(-/-)) mice at midgestation. By aggregating Shp-2(-/-) embryonic stem cells with wild-type embryos, we created Shp-2(-/-)/wild-type chimeric animals. Most chimeras had open eyelids at birth and abnormal skin development, a phenotype characteristic of mice with mutations in EGF-R signaling components. In genetic crosses, a heterozygous Shp-2 mutation dominantly enhanced the phenotype of a weak mutant allele of EGF-R (wa-2), resulting in distinctive growth retardation, developmental defects in the skin, lung, and intestine, and perinatal mortality that are reminiscent of EGF-R knockout mice. Biochemical analysis revealed that signal propagation proximal to the EGF-R upon EGF stimulation was significantly attenuated in wa-2 fibroblast cells, which was exacerbated by the additional Shp-2 mutation. Thus, we provide biological evidence here that protein-tyrosine phosphatase Shp-2 acts to enhance information flow from the EGF-R in mouse growth and development.
Qu
C K
CK
Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202-5254, USA.
Yu
W M
WM
Azzarelli
B
B
Feng
G S
GS
D000818:Animals; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D002678:Chimera / Q000235:genetics; D003433:Crosses, Genetic; D005314:Embryonic and Fetal Development / Q000235:genetics; D004789:Enzyme Activation; D066246:ErbB Receptors / Q000235:genetics* / Q000378:metabolism; D006579:Heterozygote; D006651:Histocytochemistry; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D018345:Mice, Knockout; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D009154:Mutation; D010641:Phenotype; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases / Q000235:genetics* / Q000378:metabolism; D054593:SH2 Domain-Containing Protein Tyrosine Phosphatases; D015398:Signal Transduction / Q000235:genetics*; D018909:src Homology Domains / Q000235:genetics
D047908:Intracellular Signaling Peptides and Proteins; D066246:ErbB Receptors; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases; C516725:Ptpn11 protein, mouse; C509248:Ptpn6 protein, mouse; D054593:SH2 Domain-Containing Protein Tyrosine Phosphatases