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Molecular and Cellular Biology, October 2004, p. 8951-8962, Vol. 24, No. 20
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.20.8951-8962.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Notch-Induced E2A Degradation Requires CHIP and Hsc70 as Novel Facilitators of Ubiquitination

Zhong Huang,1 Lei Nie,1 Min Xu,1,{dagger} and Xiao-Hong Sun1,2,3*

Immunobiology and Cancer Program, Oklahoma Medical Research Foundation,1 Department of Microbiology and Immunology,2 Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma3

Received 6 May 2004/ Returned for modification 17 June 2004/ Accepted 19 July 2004

E2A transcription factors, E12 and E47, are important regulators of lymphocyte development. Notch signaling pathways have been shown to regulate E2A function by accelerating the degradation of E2A proteins through a mitogen-activated protein kinase-dependent and ubiquitin-mediated pathway. To further understand the mechanism underlying E2A ubiquitination and degradation, we conducted a yeast two-hybrid screen and identified the carboxyl terminus of Hsc70-interacting protein (CHIP) as an E47 binding protein. Here, we show that CHIP associates with E2A proteins in vivo and that overexpression of CHIP induces E47 degradation in a phosphorylation-dependent manner. Conversely, knocking down CHIP with small interfering RNA alleviates Notch-induced E47 degradation. CHIP binds E47 through the E protein homology domains 2 and 3 (EHD2 and EHD3). This interaction between CHIP and E47 is independent of the U-box domain with E3 ubiquitin ligase activity but requires the chaperone binding tetratricopeptide repeats domain. The ability of CHIP to induce E47 ubiquitination and degradation correlates with its ability to bind E47. We propose that CHIP, together with its partner Hsc70, forms a preubiquitination complex (PUC) with E47 and Skp2, thus facilitating the interaction between E47 and Skp2. CHIP also associates with Cul1, which introduces PUC to the SCF E3 ligase complex, responsible for E47 ubiquitination. Therefore, CHIP plays a crucial role in the ubiquitination and degradation of E2A proteins.

* Corresponding author. Mailing address: Oklahoma Medical Research Foundation, 825 NE 13th St., Oklahoma City, OK 73104. Phone: (405) 271-7103. Fax: (405) 271-8568. E-mail: sunx{at}omrf.ouhsc.edu.

{dagger} Present address: Howard Hughes Medical Institute, Division of Infectious Diseases, University of California San Francisco, San Francisco, CA 94143.

Molecular and Cellular Biology, October 2004, p. 8951-8962, Vol. 24, No. 20
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.20.8951-8962.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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