H
IPR046370

Neurogenic mastermind-like, N-terminal domain superfamily

InterPro entry
Short nameMAML_N_sf
Overlapping entries
 

Description

This entry represents the N-terminal domain found in a family of neurogenic mastermind-like proteins (MAMLs), which act as critical transcriptional co-activators for Notch signaling
[3, 2, 12]
. Notch receptors are cleaved upon ligand engagement and the intracellular domain of Notch shuttles to the nucleus. MAMLs form a functional DNA-binding complex with the cleaved Notch receptor and the transcription factor CSL, thereby regulating transcriptional events that are specific to the Notch pathway. MAML proteins may also play roles as key transcriptional co-activators in other signal transduction pathways as well, including: muscle differentiation and myopathies (MEF2C)
[4]
, tumour suppressor pathway (p53)
[5]
and colon carcinoma survival (beta-catenin)
[6]
. MAML proteins could mediate cross-talk among the various signaling pathways and the diverse activities of the MAML proteins converge to impact normal biological processes and human diseases, including cancers.

The N-terminal domain of MAML proteins adopt an elongated kinked helix that wraps around ANK and CSL forming one of the complexes in the build-up of the Notch transcriptional complex for recruiting general transcription factors
[1]
. This N-terminal domain is responsible for its interaction with the ankyrin repeat region of the Notch proteins NOTCH1
[7]
, NOTCH2
[8]
, NOTCH3
[9]
and NOTCH4. It forms a DNA-binding complex with Notch proteins and RBPSUH/RBP-J kappa/CBF1, and also binds CREBBP/CBP
[10]
and CDK8
[11]
. The C-terminal region is required for transcriptional activation.

References

1.Structural basis for cooperativity in recruitment of MAML coactivators to Notch transcription complexes. Nam Y, Sliz P, Song L, Aster JC, Blacklow SC. Cell 124, 973-83, (2006). View articlePMID: 16530044

2.More complicated than it looks: assembly of Notch pathway transcription complexes. Kovall RA. Oncogene 27, 5099-109, (2008). View articlePMID: 18758478

3.Mastermind-like transcriptional co-activators: emerging roles in regulating cross talk among multiple signaling pathways. McElhinny AS, Li JL, Wu L. Oncogene 27, 5138-47, (2008). View articlePMID: 18758483

4.The Notch coactivator, MAML1, functions as a novel coactivator for MEF2C-mediated transcription and is required for normal myogenesis. Shen H, McElhinny AS, Cao Y, Gao P, Liu J, Bronson R, Griffin JD, Wu L. Genes Dev. 20, 675-88, (2006). View articlePMID: 16510869

5.The notch regulator MAML1 interacts with p53 and functions as a coactivator. Zhao Y, Katzman RB, Delmolino LM, Bhat I, Zhang Y, Gurumurthy CB, Germaniuk-Kurowska A, Reddi HV, Solomon A, Zeng MS, Kung A, Ma H, Gao Q, Dimri G, Stanculescu A, Miele L, Wu L, Griffin JD, Wazer DE, Band H, Band V. J. Biol. Chem. 282, 11969-81, (2007). View articlePMID: 17317671

6.Mastermind-like 1 Is a specific coactivator of beta-catenin transcription activation and is essential for colon carcinoma cell survival. Alves-Guerra MC, Ronchini C, Capobianco AJ. Cancer Res. 67, 8690-8, (2007). View articlePMID: 17875709

7.Identification of a conserved negative regulatory sequence that influences the leukemogenic activity of NOTCH1. Chiang MY, Xu ML, Histen G, Shestova O, Roy M, Nam Y, Blacklow SC, Sacks DB, Pear WS, Aster JC. Mol. Cell. Biol. 26, 6261-71, (2006). View articlePMID: 16880534

8.The transcriptional coactivator Maml1 is required for Notch2-mediated marginal zone B-cell development. Wu L, Maillard I, Nakamura M, Pear WS, Griffin JD. Blood 110, 3618-23, (2007). View articlePMID: 17699740

9.NOTCH3 expression is induced in mural cells through an autoregulatory loop that requires endothelial-expressed JAGGED1. Liu H, Kennard S, Lilly B. Circ. Res. 104, 466-75, (2009). PMID: 19150886

10.Transforming activity of MECT1-MAML2 fusion oncoprotein is mediated by constitutive CREB activation. Wu L, Liu J, Gao P, Nakamura M, Cao Y, Shen H, Griffin JD. EMBO J. 24, 2391-402, (2005). View articlePMID: 15961999

11.Mastermind recruits CycC:CDK8 to phosphorylate the Notch ICD and coordinate activation with turnover. Fryer CJ, White JB, Jones KA. Mol. Cell 16, 509-20, (2004). View articlePMID: 15546612

12.Identification of a family of mastermind-like transcriptional coactivators for mammalian notch receptors. Wu L, Sun T, Kobayashi K, Gao P, Griffin JD. Mol Cell Biol 22, 7688-700, (2002). PMID: 12370315

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