Lysine-based Structure in the Proregion of Procathepsin L Is the Recognition Site for Mannose Phosphorylation

Cuozzo, John W.; Tao, Kai; Wu, Qilong; Young, Wen; Sahagian, G. Gary

doi:10.1074/jbc.270.26.15611

Cited by 50 publications

(55 citation statements)

References 32 publications

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“…VECTORSTAIN Elite ABC kit (Rabbit IgG), DAB substrate kit for peroxidase and Hematoxylin QS were purchased from Vector Laboratories. Rabbit anti-human cathepsin D serum (Cuozzo et al, 1998), affinity-purified rabbit anti-mouse cathepsin L antibodies (Cuozzo et al, 1995), and affinity-purified rabbit anti-bovine Man-6-P/IGF-2 receptor antibodies (Tao et al, 2001) were prepared as previously described.…”

Section: Cell Linementioning

confidence: 99%

Demonstration of tumor suppression by mannose 6-phosphate/insulin-like growth factor 2 receptor

Sahagian

2004

Oncogene

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The mannose 6-phosphate/IGF-2 receptor has been proposed to be a tumor suppressor gene on the basis of loss of heterozygosity and mutations in tumors from cancer patients. To test this hypothesis, the receptor was expressed in 66cl4, a mouse mammary tumor cell line deficient in the receptor. Expression of the receptor corrected the abnormal lysosomal trafficking phenotype displayed by these cells. Receptor expression had no apparent effect on growth or invasiveness of the cells in vitro but effectively inhibited formation of mammary tumors in BALB/c mice. Analysis of cell proliferation and apoptosis in tumors indicated that the primary effect of the receptor was to inhibit cell proliferation. Proliferation indices for receptor-deficient and receptor-expressing tumors, as determined by BrdU incorporation, were 24.6 and 7.6%, respectively. No significant effect of receptor expression on apoptosis was observed. Receptor expression similarly inhibited tumor growth in BALB/c scid mice indicating that cytotoxic T cells and other components of the immune system missing in scid mice are not involved in the receptor's tumor suppressing effect. These findings establish a role for the receptor as a bona fide tumor suppressor gene and together with previous studies, suggest an important role for the receptor in human and rodent cancers.

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Section: Cell Linementioning

confidence: 99%

Demonstration of tumor suppression by mannose 6-phosphate/insulin-like growth factor 2 receptor

Sahagian

2004

Oncogene

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“…A number of studies from our laboratory and others have shown that the protein recognition domain of acid hydrolases is a complex conformation-dependent determinant that includes a number of critical lysine residues (16)(17)(18)(19)(20)(21)(22)(23). On this basis, it seems likely that the interaction of an acid hydrolase with GlcNAc-1-phosphotransferase would involve multiple contacts between the surfaces of the two proteins.…”

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confidence: 99%

The DMAP interaction domain of UDP-GlcNAc:lysosomal enzyme N -acetylglucosamine-1-phosphotransferase is a substrate recognition module

Qian

Flanagan-Steet

Meel

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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UDP-GlcNAc:lysosomal enzyme N-acetylglucosamine-1-phosphotransferase (GlcNAc-1-phosphotransferase) is an α 2 β 2 γ 2 heterohexamer that mediates the initial step in the formation of the mannose 6-phosphate recognition signal on lysosomal acid hydrolases. We previously reported that the specificity of the reaction is determined by the ability of the α/β subunits to recognize a conformationdependent protein determinant present on the acid hydrolases. We now present evidence that the DNA methyltransferase-associated protein (DMAP) interaction domain of the α subunit functions in this recognition process. First, GST-DMAP pulled down several acid hydrolases, but not nonlysosomal glycoproteins. Second, recombinant GlcNAc-1-phosphotransferase containing a missense mutation in the DMAP interaction domain (Lys732Asn) identified in a patient with mucolipidosis II exhibited full activity toward the simple sugar α-methyl D-mannoside but impaired phosphorylation of acid hydrolases. Finally, unlike the WT enzyme, expression of the K732N mutant in a zebrafish model of mucolipidosis II failed to correct the phenotypic abnormalities. These results indicate that the DMAP interaction domain of the α subunit functions in the selective recognition of acid hydrolase substrates and provides an explanation for the impaired phosphorylation of acid hydrolases in a patient with mucolipidosis II.

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“…With intracellular proteases, this processing occurs in the lytic compartment (lysosomes or vacuoles) (15); with extracellular proteases, the processing occurs during secretion (16). Targeting to the correct compartment for processing is mediated by a peptide (17) or phosphomannose (18) targeting signal on the NH 2 -terminal precursor domain that is recognized by a specific receptor that is presumed to be localized in the Golgi apparatus (19,20) to target the protein to the activating compartment.…”

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confidence: 99%

Posttranslational Removal of the Carboxyl-terminal KDEL of the Cysteine Protease SH-EP Occurs Prior to Maturation of the Enzyme

Okomoto

Minamikawa

Edward

et al. 1999

Journal of Biological Chemistry

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SH-EP is a cysteine protease from germinating mung bean (Vigna mungo) that possesses a carboxyl-terminal endoplasmic reticulum (ER) retention sequence, KDEL. In order to examine the function of the ER retention sequence, we expressed a full-length cDNA of SH-EP and a minus-KDEL control in insect Sf-9 cells using the baculovirus system. Our observations on the synthesis, processing, and trafficking of SH-EP in Sf-9 cells suggest that the KDEL ER-retention sequence is posttranslationally removed either while the protein is still in the ER or immediately after its exit from the ER, resulting in the accumulation of proSH-EP minus its KDEL signal. It is this intermediate form that appears to progress through the endomembrane system and is subsequently processed to form mature active SH-EP. The removal of an ER retention may regulate protein delivery to a functional site and present an alternative role for ER retention sequences in addition to their well established role in maintaining the protein composition of the ER lumen.SH-EP is a thiol protease expressed in germinating mung bean (Vigna mungo) cotyledons (1-3) that is among a large number of similar cysteine proteases that are synthesized after germination in order to degrade seed storage proteins (2, 4 -10). All cysteine proteases are initially synthesized as larger precursor proteins with NH 2 -terminal prodomains of approximately 120 amino acids (11). The prodomain is an inhibitor of the protease (12) and is essential in the correct folding of the protein (13). Processing of the proenzyme occurs by self-catalysis (14) in post-Golgi compartments of the secretory system. With intracellular proteases, this processing occurs in the lytic compartment (lysosomes or vacuoles) (15); with extracellular proteases, the processing occurs during secretion (16). Targeting to the correct compartment for processing is mediated by a peptide (17) or phosphomannose (18) targeting signal on the NH 2 -terminal precursor domain that is recognized by a specific receptor that is presumed to be localized in the Golgi apparatus (19,20) to target the protein to the activating compartment.SH-EP is unusual because it and a few closely related thiol proteases (21-23) are the only cysteine proteases known to possess a carboxyl-terminal ER 1 retention sequence KDEL (24 -26). Although papain superfamily proteases are widely distributed among eukaryotes (27, 28), only these plant cysteine proteases have been identified as possessing a carboxylterminal ER retention sequence. Several other legume cysteine proteases have been cloned that do not possess a KDEL tail (28 -34), indicating that even among legumes and more broadly in plants these KDEL-proteases appear to constitute a special class. Plant cells utilize both HDEL and KDEL as ER retention sequences (35)(36)(37)(38). The presence of a carboxyl-terminal KDEL in SH-EP raises a question as to whether this sequence is functional in vivo. A papain superfamily cysteine protease would appear to be an unusual putative constituent of the ER lumen, ...

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Lysine-based Structure in the Proregion of Procathepsin L Is the Recognition Site for Mannose Phosphorylation

Cited by 50 publications

References 32 publications

Demonstration of tumor suppression by mannose 6-phosphate/insulin-like growth factor 2 receptor

Demonstration of tumor suppression by mannose 6-phosphate/insulin-like growth factor 2 receptor

The DMAP interaction domain of UDP-GlcNAc:lysosomal enzyme N -acetylglucosamine-1-phosphotransferase is a substrate recognition module

Posttranslational Removal of the Carboxyl-terminal KDEL of the Cysteine Protease SH-EP Occurs Prior to Maturation of the Enzyme

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