Interaction with factor inhibiting HIF-1 defines an additional mode of cross-coupling between the Notch and hypoxia signaling pathways.
Cells adapt to hypoxia by a cellular response, where hypoxia-inducible factor 1alpha (HIF-1alpha) becomes stabilized and directly activates transcription of downstream genes. In addition to this "canonical" response, certain aspects of the pathway require integration with Notch signaling, i.e., HIF-1alpha can interact with the Notch intracellular domain (ICD) to augment the Notch downstream response. In this work, we demonstrate an additional level of complexity in this cross-talk: factor-inhibiting HIF-1 (FIH-1) regulates not only HIF activity, but also the Notch signaling output and, in addition, plays a role in how Notch signaling modulates the hypoxic response. We show that FIH-1 hydroxylates Notch ICD at two residues (N(1945) and N(2012)) that are critical for the function of Notch ICD as a transactivator within cells and during neurogenesis and myogenesis in vivo. FIH-1 negatively regulates Notch activity and accelerates myogenic differentiation. In its modulation of the hypoxic response, Notch ICD enhances recruitment of HIF-1alpha to its target promoters and derepresses HIF-1alpha function. Addition of FIH-1, which has a higher affinity for Notch ICD than for HIF-1alpha, abrogates the derepression, suggesting that Notch ICD sequesters FIH-1 away from HIF-1alpha. In conclusion, the data reveal posttranslational modification of the activated form of the Notch receptor and an intricate mode of cross-coupling between the Notch and hypoxia signaling pathways.
Zheng
Xiaofeng
X
Departments of Cell and Molecular Biology and Molecular Medicine, Karolinska Institutet, 171 77 Stockholm, Sweden.
Linke
Sarah
S
Dias
José M
JM
Zheng
Xiaowei
X
Gradin
Katarina
K
Wallis
Tristan P
TP
Hamilton
Brett R
BR
Gustafsson
Maria
M
Ruas
Jorge L
JL
Wilkins
Sarah
S
Bilton
Rebecca L
RL
Brismar
Kerstin
K
Whitelaw
Murray L
ML
Pereira
Teresa
T
Gorman
Jeffrey J
JJ
Ericson
Johan
J
Peet
Daniel J
DJ
Lendahl
Urban
U
Poellinger
Lorenz
L
D000818:Animals; D002460:Cell Line; D002642:Chick Embryo; D006801:Humans; D006900:Hydroxylation; D000860:Hypoxia / Q000378:metabolism*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D051379:Mice; D006899:Mixed Function Oxygenases; D024510:Muscle Development; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D020239:Receptor Cross-Talk; D051881:Receptor, Notch1 / Q000378:metabolism; D051883:Receptor, Notch2 / Q000378:metabolism; D000071656:Receptor, Notch3; D000074562:Receptor, Notch4; D051880:Receptors, Notch / Q000378:metabolism*; D012097:Repressor Proteins / Q000494:pharmacology; D015398:Signal Transduction; D014157:Transcription Factors / Q000494:pharmacology; D014162:Transfection
C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C497762:Notch1 protein, mouse; C497765:Notch2 protein, mouse; C499373:Notch3 protein, mouse; D011518:Proto-Oncogene Proteins; D051881:Receptor, Notch1; D051883:Receptor, Notch2; D000071656:Receptor, Notch3; D000074562:Receptor, Notch4; D051880:Receptors, Notch; D012097:Repressor Proteins; D014157:Transcription Factors; C073572:Notch4 protein, mouse; D006899:Mixed Function Oxygenases; C439790:HIF1AN protein, human