Shp-2 has a positive regulatory role in ES cell differentiation and proliferation.
Shp-2 is a ubiquitously expressed tyrosine phosphatase with two SH2 domains. Homozygous mutant mice with a targeted deletion of 65 amino acid residues in the N-terminal SH2 domain of Shp-2 die in utero at mid-gestation, with multiple defects in mesodermal patterning. To surpass the embryonic lethality in dissecting the Shp-2 function in cell growth and differentiation, we established homozygous Shp-2 mutant embryonic stem (ES) cell lines. Our previous data showed a severe suppression of hematopoietic cell differentiation from Shp-2 mutant ES cells. Here we demonstrate that development of cardiac muscle cells was dramatically delayed and impaired in embryoid bodies (EBs) of Shp-2 mutant origin. Shp-2 mutant ES cells failed to differentiate into epithelial and fibroblast cells in vitro. However, higher efficiency of secondary EB formation was observed from the mutant than the wild-type ES cells. Further, mutant ES cells were more sensitive than wild-type cells to the differentiation suppressing effect of leukemia inhibitory factor (LIF). In addition, mutant ES cells showed a reduced growth rate compared to wild-type cells. These results suggest that the Shp-2 tyrosine phosphatase is a positive regulator for both cell differentiation and proliferation, in contrast to the Src-family kinases which promote cell growth but block differentiation.
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Department of Biochemistry and Molecular Biology, Walther Oncology Center, Indiana University School of Medicine and Walther Cancer Institute, Indianapolis 46202-5121, USA.
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D000818:Animals; D002454:Cell Differentiation / Q000502:physiology*; D002455:Cell Division / Q000502:physiology*; D002460:Cell Line; D019070:Cell Lineage; D004847:Epithelial Cells / Q000166:cytology; D005347:Fibroblasts / Q000166:cytology; D005786:Gene Expression Regulation; D006131:Growth Inhibitors / Q000378:metabolism / Q000494:pharmacology; D015850:Interleukin-6; D047908:Intracellular Signaling Peptides and Proteins; D053605:Leukemia Inhibitory Factor; D008222:Lymphokines / Q000378:metabolism / Q000494:pharmacology; D051379:Mice; D017570:MyoD Protein / Q000235:genetics; D009206:Myocardium / Q000166:cytology; D018008:Myogenin / Q000235:genetics; D018995:Myosin Heavy Chains / Q000235:genetics; D018994:Myosin Light Chains / Q000235:genetics; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases / Q000235:genetics / Q000502:physiology*; D054593:SH2 Domain-Containing Protein Tyrosine Phosphatases; D015398:Signal Transduction; D018909:src Homology Domains / Q000502:physiology*
D006131:Growth Inhibitors; D015850:Interleukin-6; D047908:Intracellular Signaling Peptides and Proteins; D053605:Leukemia Inhibitory Factor; C507838:Lif protein, mouse; D008222:Lymphokines; D017570:MyoD Protein; C503801:Myog protein, mouse; D018008:Myogenin; D018994:Myosin Light Chains; 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; D018995:Myosin Heavy Chains