The tumor autocrine motility factor receptor, gp78, is a ubiquitin protein ligase implicated in degradation from the endoplasmic reticulum

doi:10.1073/pnas.251401598

The tumor autocrine motility factor receptor, gp78, is a ubiquitin protein ligase implicated in degradation from the endoplasmic reticulum

Regulation of Protein Function Laboratory, Center for Cancer Research, National Cancer Institute, Building 10, Room 1B34, 9000 Rockville Pike, Bethesda, MD 20892-1152

Edited by William J. Lennarz, State University of New York, Stony Brook, NY, and approved October 11, 2001 (received for review July 31, 2001)

Abstract

gp78, also known as the tumor autocrine motility factor receptor, is a transmembrane protein whose expression is correlated with tumor metastasis. We establish that gp78 is a RING finger-dependent ubiquitin protein ligase (E3) of the endoplasmic reticulum (ER). Consistent with this, gp78 specifically recruits MmUBC7, a ubiquitin-conjugating enzyme (E2) implicated in ER-associated degradation (ERAD), through a region distinct from the RING finger. gp78 can target itself for proteasomal degradation in a RING finger- and MmUBC7-dependent manner. Importantly, gp78 can also mediate degradation of CD3-δ, a well-characterized ERAD substrate. In contrast, gp78 lacking an intact RING finger or its multiple membrane-spanning domains stabilizes CD3-δ. gp78 has thus been found to be an example of a mammalian cellular E3 intrinsic to the ER, suggesting a potential link between ubiquitylation, ERAD, and metastasis.

Footnotes

↵ * To whom reprint requests should be addressed. E-mail: amw{at}nih.gov.
This paper was submitted directly (Track II) to the PNAS office.
Abbreviations:

ER,

endoplasmic reticulum;

HA,

hemagglutinin;

TCR,

T cell antigen receptor;

Ub,

ubiquitin;

GST,

glutathione S-transferase;

ERAD,

ER-associated degradation;

wt,

wild type;

GFP,

green fluorescent protein;

IP,

immunoprecipitation;

IB,

immunoblotting