Regulation of lymphocyte development by cell-type-specific interpretation of Notch signals.
Notch signaling pathways exert diverse biological effects depending on the cellular context where Notch receptors are activated. How Notch signaling is integrated with environmental cues is a central issue. Here, we show that Notch activation accelerates ubiquitin-mediated and mitogen-activated protein kinase (MAPK)-dependent degradation of E2A transcription factors and Janus kinases, molecules essential for both B- and T-lymphocyte development. However, these events occur in B lymphocytes, but not T lymphocytes, due to their different levels of MAPK, thus providing one mechanism whereby Notch inhibits B-cell development without impairing T-cell differentiation. Lymphoid progenitors expressing a Notch-resistant E2A mutant differentiated into B-lineage cells on stromal cells expressing Notch ligands and in the thymus of transplant recipients. Bone marrow transplant assays and examination of steady-state B lymphopoiesis also revealed that the expression of Notch-resistant E2A and constitutively active STAT5 in mice neutralized the effects of Notch-induced degradation, allowing B-cell development through a bone marrow-like program in the thymus. These findings illustrate that Notch function can be influenced by MAPKs, producing distinct outcomes in different cellular contexts.
Nie
Lei
L
Program in Immunobiology and Cancer Research, Oklahoma Medical Research Foundation, 825 NE 13th Street, Oklahoma City, OK 73104, USA.
Perry
S Scott
SS
Zhao
Ying
Y
Huang
Jiaxue
J
Kincade
Paul W
PW
Farrar
Michael A
MA
Sun
Xiao-Hong
XH
D000818:Animals; D016175:B-Lymphocyte Subsets / Q000166:cytology*; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000502:physiology*; D016026:Bone Marrow Transplantation; D002135:Calcium-Binding Proteins; D002460:Cell Line; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000502:physiology; D053612:Janus Kinases / Q000378:metabolism; D038041:Lymphopoiesis / Q000502:physiology*; D020935:MAP Kinase Signaling System / Q000502:physiology; D008565:Membrane Proteins / Q000235:genetics / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011828:Radiation Chimera; D051881:Receptor, Notch1 / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000502:physiology; D050799:STAT5 Transcription Factor / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D017154:Stromal Cells / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000166:cytology; D013950:Thymus Gland / Q000166:cytology; D025801:Ubiquitin / Q000378:metabolism
D051792:Basic Helix-Loop-Helix Proteins; D002135:Calcium-Binding Proteins; D036341:Intercellular Signaling Peptides and Proteins; D053612:Janus Kinases; D008565:Membrane Proteins; D046988:Proteasome Endopeptidase Complex; D051881:Receptor, Notch1; D011993:Recombinant Fusion Proteins; D050799:STAT5 Transcription Factor; D025801:Ubiquitin; C512941:DLK1 protein, human; C497762:Notch1 protein, mouse; C075668:Tcf3 protein, mouse