Tumor suppression by phospholipase C-beta3 via SHP-1-mediated dephosphorylation of Stat5.
Given its catalytic activity to generate diacylglycerol and inositol 1,4,5-trisphosphate, phospholipase C (PLC) is implicated in promoting cell growth. However, we found that PLC-beta3-deficient mice develop myeloproliferative disease, lymphoma, and other tumors. The mutant mice have increased numbers of hematopoietic stem cells with increased proliferative, survival, and myeloid-differentiative abilities. These properties are dependent on Stat5 and can be antagonized by the protein phosphatase SHP-1. Stat5-dependent cooperative transformation by active c-Myc and PLC-beta3 deficiency was suggested in mouse lymphomas in PLC-beta3(-/-) and in Emicro-myc;PLC-beta3(+/-) mice and human Burkitt's lymphoma cells. The same mechanism for malignant transformation seems to be operative in other human lymphoid and myeloid malignancies. Thus, PLC-beta3 is likely a tumor suppressor.
Xiao
Wenbin
W
Division of Cell Biology, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA.
Hong
Hong
H
Kawakami
Yuko
Y
Kato
Yuko
Y
Wu
Dianqing
D
Yasudo
Hiroki
H
Kimura
Akiko
A
Kubagawa
Hiromi
H
Bertoli
Luigi F
LF
Davis
Randall S
RS
Chau
Luan A
LA
Madrenas
Joaquin
J
Hsia
Cyrus C
CC
Xenocostas
Anargyros
A
Kipps
Thomas J
TJ
Hennighausen
Lothar
L
Iwama
Atsushi
A
Nakauchi
Hiromitsu
H
Kawakami
Toshiaki
T
D000818:Animals; D002454:Cell Differentiation; D002470:Cell Survival / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D006412:Hematopoietic Stem Cells / Q000378:metabolism / Q000473:pathology; D008223:Lymphoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D009154:Mutation; D009196:Myeloproliferative Disorders / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D054799:Phospholipase C beta / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D010766:Phosphorylation; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D050799:STAT5 Transcription Factor / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D015398:Signal Transduction; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
D016271:Proto-Oncogene Proteins c-myc; D050799:STAT5 Transcription Factor; D025521:Tumor Suppressor Proteins; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; C509248:Ptpn6 protein, mouse; D054799:Phospholipase C beta