Noonan syndrome/leukemia-associated gain-of-function mutations in SHP-2 phosphatase (PTPN11) enhance cell migration and angiogenesis.
Mutations in SHP-2 phosphatase (PTPN11) that cause hyperactivation of its catalytic activity have been identified in Noonan syndrome and various childhood leukemias. Recent studies suggest that the gain-of-function (GOF) mutations of SHP-2 play a causal role in the pathogenesis of these diseases. However, the molecular mechanisms by which GOF mutations of SHP-2 induce these phenotypes are not fully understood. Here, we show that GOF mutations in SHP-2, such as E76K and D61G, drastically increase spreading and migration of various cell types, including hematopoietic cells, endothelial cells, and fibroblasts. More importantly, in vivo angiogenesis in SHP-2 D61G knock-in mice is also enhanced. Mechanistic studies suggest that the increased cell migration is attributed to the enhanced beta1 integrin outside-in signaling. In response to beta1 integrin cross-linking or fibronectin stimulation, activation of ERK and Akt kinases is greatly increased by SHP-2 GOF mutations. Also, integrin-induced activation of RhoA and Rac1 GTPases is elevated. Interestingly, mutant cells with the SHP-2 GOF mutation (D61G) are more sensitive than wild-type cells to the suppression of cell motility by inhibition of these pathways. Collectively, these studies reaffirm the positive role of SHP-2 phosphatase in cell motility and suggest a new mechanism by which SHP-2 GOF mutations contribute to diseases.
Wang
Siying
S
Department of Medicine, Division of Hematology/Oncology, Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio 44106, USA.
Yu
Wen-Mei
WM
Zhang
Wanming
W
McCrae
Keith R
KR
Neel
Benjamin G
BG
Qu
Cheng-Kui
CK
D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics*; D015971:Gene Expression Regulation, Enzymologic / Q000235:genetics; D007938:Leukemia / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D009389:Neovascularization, Pathologic / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D009634:Noonan Syndrome / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11