Role of SHP-2 tyrosine phosphatase in the DNA damage-induced cell death response.
SHP-2, a ubiquitously expressed Src hmology 2 (SH2) domain-containing tyrosine phosphatase, plays a critical role in the regulation of growth factor and cytokine signal transduction. Here we report a novel function of this phosphatase in DNA damage-induced cellular responses. Mutant embryonic fibroblast cells lacking functional SHP-2 showed significantly decreased apoptosis in response to DNA damage. Following cisplatin treatment, induction of p73 and its downstream effector p21(Cip1) was essentially blocked in SHP-2 mutant cells. Further investigation revealed that activation of the nuclear tyrosine kinase c-Abl, an essential mediator in DNA damage induction of p73, was impaired in the mutant cells, suggesting a functional requirement of SHP-2 in c-Abl activation. Consistent with this observation, the effect of overexpression of c-Abl kinase in SHP-2 mutant cells on sensitizing the cells to DNA damage-induced death was abolished. Additionally, we found that in embryonic fibroblast cells 30-40% of SHP-2 was localized in the nuclei, and that a fraction of nuclear SHP-2 was constitutively associated with c-Abl via its SH3 domain. Phosphatase activity of nuclear but not cytoplasmic SHP-2 was significantly enhanced in response to DNA damage. These results together suggest a novel nuclear function for SHP-2 phosphatase in the regulation of DNA damage-induced apoptotic responses.
Yuan
Liangping
L
Departments of Hematopoiesis and Experimental Pathology, Holland Laboratory, American Red Cross, Rockville, Maryland 20855, USA.
Yu
Wen-Mei
WM
Yuan
Zhimin
Z
Haudenschild
Christian C
CC
Qu
Cheng-Kui
CK
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000096:biosynthesis; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000096:biosynthesis; D004622:Embryo, Mammalian / Q000166:cytology; D005347:Fibroblasts / Q000166:cytology / Q000201:enzymology; D005786:Gene Expression Regulation / Q000187:drug effects; D016147:Genes, Tumor Suppressor; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D018345:Mice, Knockout; D009153:Mutagens / Q000494:pharmacology; D009687:Nuclear Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D017027:Protein Tyrosine Phosphatases / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D016315:Proto-Oncogene Proteins c-abl / Q000378:metabolism; D054593:SH2 Domain-Containing Protein Tyrosine Phosphatases; D015398:Signal Transduction; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins
C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D009153:Mutagens; D009687:Nuclear Proteins; C000606368:Trp73 protein, mouse; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins; D016315:Proto-Oncogene Proteins c-abl; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D017027:Protein Tyrosine Phosphatases; C516725:Ptpn11 protein, mouse; D054593:SH2 Domain-Containing Protein Tyrosine Phosphatases; D002945:Cisplatin