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The type III TGF-? receptor betaglycan transmembrane-cytoplasmic domain fragment is stable after ectodomain cleavage and is a substrate of the intramembrane protease ?-secretase.

ABSTRACT: The Type III TGF-? receptor, betaglycan, is a widely expressed proteoglycan co-receptor for TGF-? superfamily ligands. The full-length protein undergoes ectodomain cleavage with release of a soluble ectodomain fragment. The fate of the resulting transmembrane-cytoplasmic fragment, however, has never been explored. We demonstrate here that the transmembrane-cytoplasmic fragment is stable in transfected cells and in cell lines expressing endogenous betaglycan. Production of this fragment is inhibited by the ectodomain shedding inhibitor TAPI-2. Treatment of cells with inhibitors of the intramembrane protease ?-secretase stabilizes this fragment, suggesting that it is a substrate of ?-secretase. Expression of the transmembrane-cytoplasmic fragment as well as ?-secretase inhibitor stabilization are independent of TGF-?1 or -?2 and are unaffected by mutation of the cytoplasmic domain serines that undergo phosphorylation. ?-Secretase inhibition or the expression of a transmembrane-cytoplasmic fragment in HepG2 cells blunted TGF-?2 signaling. Our findings thus suggest that the transmembrane-cytoplasmic fragment remaining after betaglycan ectodomain cleavage is stable and a substrate of ?-secretase, which may have significant implications for the TGF-? signaling response.

SUBMITTER: Blair CR

PROVIDER: S-EPMC3026071 | biostudies-literature | 2011 Feb

REPOSITORIES: biostudies-literature

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The type III TGF-β receptor betaglycan transmembrane-cytoplasmic domain fragment is stable after ectodomain cleavage and is a substrate of the intramembrane protease γ-secretase.

Blair Cheyne R CR Stone Jacqueline B JB Wells Rebecca G RG

Biochimica et biophysica acta 20101215 2

The Type III TGF-β receptor, betaglycan, is a widely expressed proteoglycan co-receptor for TGF-β superfamily ligands. The full-length protein undergoes ectodomain cleavage with release of a soluble ectodomain fragment. The fate of the resulting transmembrane-cytoplasmic fragment, however, has never been explored. We demonstrate here that the transmembrane-cytoplasmic fragment is stable in transfected cells and in cell lines expressing endogenous betaglycan. Production of this fragment is inhibi ...[more]

PMID: 21167215

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Project description:BackgroundAlcadein proteins (Alcs; Alc?, Alc?and Alc?) are predominantly expressed in neurons, as is Alzheimer's ?-amyloid (A?) precursor protein (APP). Both Alcs and APP are cleaved by primary ?- or ?-secretase to generate membrane-associated C-terminal fragments (CTFs). Alc CTFs are further cleaved by ?-secretase to secrete p3-Alc peptide along with the release of intracellular domain fragment (Alc ICD) from the membrane. In the case of APP, APP CTF? is initially cleaved at the ?-site to release the intracellular domain fragment (AICD) and consequently the ?-site is determined, by which A? generates. The initial ?-site is thought to define the final ?-site position, which determines whether A?40/43 or A?42 is generated. However, initial intracellular ?-cleavage sites of Alc CTF to generate Alc ICD and the molecular mechanism that final ?-site position is determined remains unclear in Alcs.MethodologyUsing HEK293 cells expressing Alcs plus presenilin 1 (PS1, a catalytic unit of ?-secretase) and the membrane fractions of these cells, the generation of p3-Alc possessing C-terminal ?-cleavage site and Alc ICD possessing N-terminal ?-cleavage site were analysed with MALDI-TOF/MS. We determined the initial ?-site position of all Alc?, Alc? and Alc?, and analyzed the relationship between the initially determined ?-site position and the final ?-cleavage position.ConclusionsThe initial ?-site position does not always determine the final ?-cleavage position in Alcs, which differed from APP. No additional ?-cleavage sites are generated from artificial/non-physiological positions of ?-cleavage for Alcs, while the artificial ?-cleavage positions can influence in selection of physiological ?-site positions. Because alteration of ?-secretase activity is thought to be a pathogenesis of sporadic Alzheimer's disease, Alcs are useful and sensitive substrate to detect the altered cleavage of substrates by ?-secretase, which may be induced by malfunction of ?-secretase itself or changes of membrane environment for enzymatic reaction.

Dataset Information

The type III TGF-? receptor betaglycan transmembrane-cytoplasmic domain fragment is stable after ectodomain cleavage and is a substrate of the intramembrane protease ?-secretase.

Publications

The type III TGF-β receptor betaglycan transmembrane-cytoplasmic domain fragment is stable after ectodomain cleavage and is a substrate of the intramembrane protease γ-secretase.

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